This invention relates to peptidyl cysteine protease inhibitors. The compounds are reversible inhibitors of the cysteine proteases S, K, F, L and B and are therefore useful in the treatment of autoimmune and other cathepsin related diseases. The invention also discloses processes for preparing such compounds and pharmaceutical compositions comprising them.
Cathepsin S and cathepsin K are members of the papain family, within the papain superfamily of cysteine proteases. The papain family is the largest group of cysteine proteases and includes proteases such as cathepsins B, H, K, L, O and S. (A. J. Barrett et al., 1996, Perspectives in Drug Discovery and Design, 6, 1). The cysteine proteases have important roles in human biology and diseases including atherosclerosis, emphysema, osteoporosis, chronic inflammation and immune disorders (H. A. Chapman et al., 1997, Ann. Rev. Physiol., 59, 63). Cathepsin S plays a key role in regulating antigen presentation and immunity (H. A. Chapman, 1998, Current Opinion in Immunology, 10, 93; R. J. Riese et al., 1998, J. Clin. Invest., 101, 2351; R. J. Riese et al., 1996, Immunity, 4, 357). Cathepsin S deficient mice have impaired invariant chain degradation resulting in decreased antigen presentation and germinal center formation, and diminished susceptibility to collagen-induced arthritis indicating the therapeutic potential for a cathepsin S inhibitor (G. Shi et al., 1999, Immunity, 10, 197; T. Y. Nakagawa et al, 1999, Immunity, 10, 207)
The specificity of the immune response relies on processing of foreign protein and presentation of antigenic peptide at the cell surface. Antigenic peptide is presented bound to MHC Class II, a heterodimeric glycoprotein expressed in certain antigen presenting cells of hematopoietic lineage, such as B cells, macrophages and dendritic cells. Presentation of antigen to effector cells, such as T-cells, is a fundamental step in recognition of non-self and thus initiation of the immune response.
Recently MHC Class II heterodimers were shown to associate intracellularly with a third molecule designated invariant chain. Invariant chain facilitates Class II transport to the endosomal compartment and stabilizes the Class II protein prior to loading with antigen. Invariant chain interacts directly with Class II dimers in the antigen-binding groove and therefore must be proteolyzed and removed or antigen cannot be loaded or presented. Current research suggests that invariant chain is selectively proteolyzed by cathepsin S, which is compartmentalized with MHC Class II complexes within the cell. Cathepsin S degrades invariant chain to a small peptide, termed CLIP, which occupies the antigen-binding groove. CLIP is released from MHC Class II by the interaction of MHC Class II with HLA-DM, a MHC-like molecule thus freeing MHC Class II to associate with antigenic peptides. MHC Class II-antigen complexes are then transported to the cell surface for presentation to T-cells, and initiation of the immune response.
Cathepsin S, through proteolytic degradation of invariant chain to CLIP, provides a fundamental step in generation of an immune response. It follows that inhibition of antigen presentation via prevention of invariant chain degradation by cathepsin S could provide a mechanism for immuno-regulation. Control of antigen-specific immune responses has long been desirable as a useful and safe therapy for autoimmune diseases. Such diseases include Crohn""s disease and arthritis, as well as other T-cell-mediated immune responses (C. Janeway and P. Travers, 1996, Immunobiology, The Immune System in Health and Disease, Chapter 12). Furthermore, cathepsin S, which has broad pH specificity, has been implicated in a variety of other diseases involving extracellular proteolysis, such as Alzheimer""s disease (U. Muller-Ladner et al., 1996, Perspectives in Drug Discovery and Design, 6, 87) and atherosclerosis (G. K. Sukhova et al., 1998, J. Clin. Invest., 102, 576).
A cathepsin S inhibitor has been found to block the rise in IgE titers and eosinophil infiltration in the lung in a mouse model of pulmonary hypersensitivity, suggesting that cathepsin S may be involved in asthma (R. J. Riese et al., J. Clin. Investigation,1998, 101, 2351).
Another cysteine protease, cathepsin F has been found in macrophages and is also involved in antigen processing. It has been postulated that cathepsin F in stimulated lung macrophages and possibly other antigen presenting cells could play a role in airway inflammation (G.-P. Shi et al., J. Exp. Med., 2000, 191, 1177).
Cathepsin K, another cysteine protease has been found to be highly expressed in osteoclasts and to degrade bone collagen and other bone matrix proteins. Inhibitors of cathepsin K have been shown to inhibit bone resorption in mice. Therefore, cathepsin K may play a role in osteoclastic bone resorption and cathepsin K inhibitors may be useful in the treatment of diseases involving bone resorption such as osteoporosis (F. Lazner et al., Human Molecular Genetics, 1999, 8, 1839).
Cysteine proteases are characterized by having a cysteine residue at the active site which serves as a nucleophile. The active site also contains a histidine residue. The imidazole ring on the histidine serves as a base to generate a thiolate anion on the active site cysteine, increasing its nucleophilicity. When a substrate is recognized by the protease, the amide bond to be cleaved is directed to the active site, where the thiolate attacks the carbonyl carbon forming an acyl-enzyme intermediate and cleaving the amide bond, liberating an amine. Subsequently, water cleaves the acyl-enzyme species regenerating the enzyme and liberating the other cleavage product of the substrate, a carboxylic acid.
Inhibitors of cysteine proteases contain a functionality that can react reversibly or irreversibly with the active site cysteine. Examples of reactive functionalities that have been described (D. Rasnick, 1996, Perspectives in Drug Discovery and Design, 6, 47) on cysteine protease inhibitors include peptidyl diazomethanes, epoxides, monofluoroalkanes and acyloxymethanes, which irreversibly alkylate the cysteine thiol. Other irreversible inhibitors include Michael acceptors such as peptidyl vinyl esters and other carboxylic acid derivatives (S. Liu et al., J. Med Chem., 1992, 35, 1067) and vinyl sulfones (J. T. Palmer et al., 1995, J. Med Chem., 38, 3193).
Reactive functionalities that form reversible complexes with the active site cysteine include peptidyl aldehydes (R. P. Hanzlik et al., 1991, Biochim. Biophys. Acta., 1073, 33), which are non-selective, inhibiting both cysteine and serine proteases as well as other nucleophiles. Peptidyl nitriles (R. P. Hanzlik et al., 1990, Biochim. Biophys. Acta., 1035, 62) are less reactive than aldehydes and therefore more selective for the more nucleophilic cysteine proteases. Various reactive ketones have also been reported to be reversible inhibitors of cysteine proteases (D. Rasnick, 1996, ibid). In addition to reacting with the nucleophilic cysteine of the active site, reactive ketones may react with water, forming a hemiketal which may act as a transition state inhibitor.
Examples of cathepsin S inhibitors have been reported. J. L. Klaus et al. (WO 9640737) described reversible inhibitors of cysteine proteases including cathepsin S, containing an ethylene diamine. In U.S. Pat. No. 5,776,718 to Palmer et al. there is disclosed in it""s broadest generic aspect a protease inhibitor comprising a targeting group linked through a two carbon atom chain to an electron withdrawing group (EWG). The compounds of the present application are structurally distinct and thus excluded from the 5,776,718 patent with particular embodiments possessing unexpectedly greater activity than the closest compounds of the prior art. Other examples of cathepsin S inhibitors have been reported by E. T. Altmann et al, (WO 9924460, 1999) which describes dipeptide nitriles asserted to have activity as inhibitors of Cathepsins B, K, L and S. The WO publication does not disclose any compounds possessing a succinate structure.
Additional peptidyl nitriles have been reported as protease inhibitors. For example, both nitrites and ketoheterocycles are described by B. A. Rowe et al. (U.S. Pat. No. 5,714,471) as protease inhibitors useful in the treatment of neurodegenerative diseases. Peptidyl nitrites are reported by B. Malcolm et al. (WO 9222570) as inhibitors of picornavirus protease. B. J. Gour-Salin (Can. J. Chem., 1991, 69, 1288) and T. C. Liang (Arch. Biochim. Biophys., 1987, 252, 626) described peptidyl nitriles as inhibitors of papain
A reversible inhibitor presents a more attractive therapy than irreversible inhibitors. Even compounds with high specificity for a particular protease can bind non-target enzymes. An irreversible compound could therefore permanently inactivate a non-target enzyme, increasing the likelihood of toxicity. Furthermore, any toxic effects resulting from inactivation of the target enzyme would be mitigated by reversible inhibitors, and could be easily remedied by modified or lower dosing. Finally, covalent modification of an enzyme by an irreversible inhibitor could potentially generate an antibody response by acting as a hapten.
In light of the above, there is a clear need for compounds which reversibly and selectively inhibit cysteine proteases such as cathepsin S, K, F, L and cathepsin B for indications in which these proteases exacerbate disease.
It is therefore an object of this invention to provide novel compounds according to the formulas (I) and (Ia) as described herein which reversibly inhibit the cysteine proteases cathepsin S, K, F, L and cathepsin B. It is a further object of the invention to provide methods for treating diseases and pathological conditions exacerbated by these cysteine proteases such as, but not limited, to rheumatoid arthritis, asthma and osteoporosis. It is yet a further object of the invention to provide novel processes for preparation of the above-mentioned novel compounds.
The novel compounds of the invention are derivatives of succinamide and are therefore less peptidic in nature than many of the protease inhibitors described in the prior art. These compounds, then, may exhibit certain advantages over known peptidic like compounds. These advantages may include, for example, increased bioavailability, increased stability, increased half-life and decreased clearance rates.
A proposed mechanism of action of the cysteine protease inhibitors of this invention is that the inhibitors contain a functionality that can react (reversibly or irreversibly) with the active site cysteine. The reactive functionality is attached to a peptide or peptide mimic that can be recognized and accommodated by the region of the protease surrounding the active site. The nature of both the reactive functionality and the remaining portion of the inhibitor determine the degree of selectivity and potency toward a particular protease.
Given the similarity of the active sites in cysteine proteases, it may be anticipated that a given class of inhibitors might have activity against more that one cysteine protease. It may also be expected that due to structural differences between individual cysteine proteases, different compounds of the invention may have different inhibitory potencies against different cysteine proteases. Thus some of the compounds of the invention may also be expected to be most effective in treating diseases mediated by cysteine proteases that they inhibit most potently. The activity of particular compounds disclosed herein against cysteine proteases cathepsin S, K, F, L and cathepsin B may be determined by the screens described in the section entitled xe2x80x9cAssessment of Biological Properties.xe2x80x9d
Accordingly, in the first generic aspect of the invention, there is provided compounds of formula (I): 
wherein:
A is xe2x80x94C(O)xe2x80x94 or xe2x80x94CH(OR8)xe2x80x94;
R1 is alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl or amino wherein R1 is optionally substituted by one or more Ra;
Ra is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, aryloxy, alkanoyl, aroyl, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by alkyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylthio arylthio, ureido wherein either nitrogen atom may be independently substituted by alkyl, aryl, heterocyclyl or heteroaryl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, arylsulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may be independently mono or di-substituted by alkyl, aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; Ra may be further optionally substituted by one or more Rb;
Rb is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, arylalkyl, alkoxy, aryloxy, arylalkoxy, alkanoyl, aroyl, amino wherein the nitrogen atom may be independently mono or di-substituted by alkyl, aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino;
R2 is hydrogen, ORi or lower alkyl;
R3 is hydrogen or lower alkyl;
R4 is hydrogen or lower alkyl;
R5 is hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein R5 is optionally substituted by one or more Rc;
Rc is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, aryloxy, arylalkoxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyl, aroyl, alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by alkyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylthio, arylthio, ureido wherein either nitrogen atom may be independently substituted by alkyl, aryl, heterocyclyl or heteroaryl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, arylsulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may be independently mono or di-substituted by alkyl, aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rc may be further optionally substituted by one or more Rd;
Rd is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkyl, alkoxy, aryloxy, arylalkoxy, alkanoyl, aroyl, amino, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino;
R6 is hydrogen or lower alkyl said alkyl being optionally interrupted by 1 to two heteroatoms selected from the group consisting of N,O and S;
R7 is hydrogen, alkyl said alkyl being optionally interrupted by 1 to two heteroatoms selected from the group consisting of N,O and S, cycloalkyl, aryl, heterocyclyl, aryl, heteroaryl or cyano, wherein R7 is optionally substituted by one or more Re;
Re is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, aryloxy, arylalkoxy, alkanoyl, aroyl, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy, heteroarylalkoxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by alkyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylcarbamoyl, arylcarbamoyl, alkylthio, arylthio, arylalkylthio, ureido wherein either nitrogen atom may be independently substituted by alkyl, aryl, heterocyclyl or heteroaryl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, arylsulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may be independently mono or di-substituted by alkyl, aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Re may be further optionally substituted by one or more Rf;
Rf is selected from the group consisting of alkyl, cycloalkyl, aryl optionally substituted by one or more groups selected from halogen, methyl or methoxy, heterocyclyl, heteroaryl, alkoxy, aryloxy, arylalkoxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by alkyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylcarbamoyl, arylcarbamoyl, alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, arylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, ureido wherein either nitrogen atom may be independently substituted by alkyl, aryl, heterocyclyl or heteroaryl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, arylsulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may be independently mono or di-substituted by alkyl, aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino;
or R6 and R7 together with the carbon they are attached form a 4 to 7 membered carbocyclic or heterocyclic ring, the carbocyclic or heterocyclic ring being optionally substituted with one or more Rg;
Rg is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, imidazolyl and pyridinyl, C1-5 alkanoyl, aroyl, C1-5 alkoxycarbonyl, aryloxycarbonyl, carbamoyl wherein the nitrogen atom may be independantly mono or disubstituted by C1-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, thiazolyl, imidazolyl, pyridinyl, benzimidazolyl and quinolinyl, C1-5 alkanoylamino, aroylamino, C1-5 alkylthio, arylthio, C1-5 alkylsulfonylamino, arylsulfonylamino, C1-5 alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may be independently mono or disubstituted by alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rg may be further optionally substituted by one or more Rh;
Rh is selected from the group consisting of C1-5 alkyl, C3-6 cycloalkyl, aryl optionally substituted by one or more groups selected from halogen, lower alkyl or lower alkoxy, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl and thiopyranyl, heteroaryl selected from the group consisting of furanyl, thienyl pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, benzoxazolyl and quinoxalinyl, C1-5 alkoxy, aryloxy, amino wherein the nitrogen atom may be independently mono or di-substituted by alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl and morpholinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl and pyridinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino;
R8 is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl or aryl-alkyl;
Ri is hydrogen or lower alkyl;
X is O or S and
pharmaceutically acceptable salts, esters or tautomers thereof.
Preferred are compounds of the formula (I) wherein:
A is as defined above;
R1 is C1-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl and thiopyranyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl and amino wherein R1 is optionally substituted by one or more Ra;
Ra is selected from the group consisting of C1-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, C1-8 alkoxy, aryloxy, C1-8 alkoxycarbonyl, aryloxycarbonyl, C1-8 alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-8 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, C1-8 alkanoylamino, aroylamino, C1-8 alkylthio, arylthio, ureido wherein either nitrogen atom may be independently substituted by alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, arylsulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may be independently mono or di-substituted by alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; Ra may be further optionally substituted by one or more Rb;
Rb is selected from the group consisting of C1-8 alkyl, C3-6 cycloalkyl, aryl, C1-8 alkoxy, aryloxy, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino;
R2 is hydrogen, ORi or C1-5 alkyl;
R3 is hydrogen or C1-5 alkyl;
R4 is hydrogen or C1-5 alkyl;
R5 is hydrogen, C1-8 alkyl, C3-7 cycloalkyl or aryl wherein R5 is optionally substituted by one or more Rc;
Rc is selected from the group consisting of C1-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, C1-8 alkoxy, aryloxy, alkanoyl, aroyl, C1-8 alkoxycarbonyl, aryloxycarbonyl, C1-8 alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-8 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, C1-8 alkanoylamino, aroylamino, C1-8 alkylthio, arylthio, ureido wherein either nitrogen atom may be independently substituted by alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, arylsulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may be independently mono or di-substituted by alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rc may be further optionally substituted by one or more Rd;
Rd is selected from the group consisting of C1-8 alkyl, C3-6 cycloalkyl, aryl, arylalkyl, C1-8 alkoxy, aryloxy, arylalkoxy, aroyl, amino, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino;
R7 is hydrogen, C1-8 alkyl said alkyl being optionally interrupted by 1 to two heteroatoms selected from the group consisting of N,O and S, C3-7 cycloalkyl, aryl or cyano, wherein R7 is optionally substituted by one or more Re;
Re is selected from the group consisting of C1-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, C1-8 alkoxy, aryloxy, arylC1-8alkoxy, heteroarylC1-8alkoxy, C1-8 alkoxycarbonyl, aryloxycarbonyl, C1-8 alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-8 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, C1-8 alkanoylamino, aroylamino, C1-8 alkylthio, arylthio, arylC1-8 alkylthio, ureido wherein either nitrogen atom may be independently substituted by alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, arylsulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may be independently mono or di-substituted by alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Re may be further optionally substituted by one or more Rf;
Rf is selected from the group consisting of C1-8 alkyl, C3-7 cycloalkyl, aryl optionally substituted by one or more groups selected from halogen, methyl or methoxy, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, C1-8 alkoxy, aryloxy, arylC1-8alkoxy, C1-8 alkoxycarbonyl, aryloxycarbonyl, C1-8 alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-8 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, C1-8 alkanoylamino, aroylamino, C1-8 alkylthio, arylthio, ureido wherein either nitrogen atom may be independently substituted by alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, arylsulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may be independently mono or di-substituted by alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino;
or R6 and R7 together with the carbon they are attached form a 4 to 7 membered carbocyclic or heterocyclic ring, the carbocyclic or heterocyclic ring being optionally substituted with one or more Rg;
Rg is selected from the group consisting of alkyl, cycloalkyl, phenyl, heteroaryl selected from the group consisting of furanyl, thienyl and pyridinyl, C1-5alkanoyl, aroyl, C1-5alkoxycarbonyl, aryloxycarbonyl, carbamoyl wherein the nitrogen atom may be independantly mono or disubstituted by C1-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, thiazolyl, imidazolyl, pyridinyl, benzimidazolyl and quinolinyl, C1-5 alkylthio wherein the sulfur atom may be oxidised to a sulfoxide or sulfone, arylthio wherein the sulfur atom may be oxidised to a sulfoxide or sulfone, C1-5 alkylaminosulfonyl, arylaminosulfonyl, halogen, hydroxy, oxo, carboxy and cyano, Rg may be further optionally substituted by one or more Rh;
Rh is selected from the group consisting of C1-5 alkyl, C3-6 cycloalkyl, aryl optionally substituted by one or more groups selected from halogen, C1-5 alkyl or C1-5 alkoxy, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl, heteroaryl selected from the group consisting of furanyl, thienyl pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, benzoxazolyl and quinoxalinyl, C1-5 alkoxy, aryloxy, amino wherein the nitrogen atom may be independently mono or di-substituted by alkyl, aryl, heterocyclyl selected from the group consisting of piperidinyl and morpholinyl or heteroaryl selected from the group consisting of furanyl, thienyl and pyridinyl, halogen, hydroxy, oxo, carboxy and cyano;
R8 is hydrogen, alkyl, cycloalkyl-alkyl or arylalkyl;
Ri is hydrogen or C1-8 alkyl and
X is O or S.
More preferred are compounds of the formula (I) as described immediately above and wherein:
A is as defined above;
R1 is C1-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl and thiopyranyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl or amino; wherein R1 is optionally substituted by one or more Ra;
Ra is selected from the group consisting of C1-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl;, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, C1-5 alkoxy, aryloxy, C1-5 alkoxycarbonyl, aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-8 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, C1-5 alkanoylamino, aroylamino, C1-5 alkylthio, arylthio, ureido wherein either nitrogen atom may be independently substituted by alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, C1-5 alkoxycarbonylamino, aryloxycarbonylamino, C1-5 alkylcarbamoyloxy, arylcarbamoyloxy, C1-5 alkylsulfonylamino, arylsulfonylamino, C1-5 alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may be independently mono or di-substituted by alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Ra may be further optionally substituted by one or more Rb;
Rb is selected from the group consisting of C1-5 alkyl, C3-6 cycloalkyl, aryl, C1-5 alkoxy, aryloxy, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino;
R2 is hydrogen, ORi or C1-3 alkyl;
R3 is hydrogen or C1-3 alkyl;
R4 is hydrogen or C1-3 alkyl;
R5 is hydrogen, C1-5 alkyl, C3-7 cycloalkyl or aryl wherein R5 is optionally substituted by one or more Rc;
Rc is selected from the group consisting of C1-5 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, C1-5 alkoxy, aryloxy, C1-5 alkanoyl, aroyl, C1-5 alkoxycarbonyl, aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, C1-5 alkanoylamino, aroylamino, C1-5 alkylthio, arylthio, ureido wherein either nitrogen atom may be independently substituted by C1-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, C1-5 alkoxycarbonylamino, aryloxycarbonylamino, C1-5 alkylcarbamoyloxy, arylcarbamoyloxy, C1-5 alkylsulfonylamino, arylsulfonylamino, C1-5 alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo, carboxy, cyano, amidino and guanidino, Rc may be further optionally substituted by one or more Rd;
Rd is selected from the group consisting of C1-5 alkyl, C3-6 cycloalkyl, aryl, arylalkyl, C1-5 alkoxy, aryloxy, arylC1-5alkoxy, aroyl, amino, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino;
R6 is hydrogen or C1-8 alkyl said alkyl being optionally interrupted by 1 to two heteroatoms selected from the group consisting of N,O and S;
R7 is hydrogen, C1-5 alkyl said alkyl being optionally interrupted by 1 to two heteroatoms selected from the group consisting of N,O and S, C3-7 cycloalkyl, aryl or cyano, wherein R7 is optionally substituted by one or more Re;
Re is selected from the group consisting of C1-5 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, C1-5 alkoxy, aryloxy, arylC1-5alkoxy, heteroarylC1-5alkoxy, C1-5 alkoxycarbonyl, aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, C1-5 alkanoylamino, aroylamino, C1-5 alkylthioarylthioarylC1-5 alkylthio, ureido wherein either nitrogen atom may be independently substituted by C1-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, C1-5 alkoxycarbonylamino, aryloxycarbonylamino, C1-5 alkylcarbamoyloxy, arylcarbamoyloxy, C1-5 alkylsulfonylamino, arylsulfonylamino, C1-5 alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Re may be further optionally substituted by one or more Rf;
Rf is selected from the group consisting of C1-5 alkyl, C3-7 cycloalkyl, aryl optionally substituted by one or more groups selected from halogen, methyl or methoxy, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, C1-5 alkoxy, aryloxy, arylC1-5alkoxy, C1-5 alkoxycarbonyl, aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, C1-5 alkanoylamino, aroylamino, C1-5 alkylthio, arylthio, ureido wherein either nitrogen atom may be independently substituted by C1-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, C1-5 alkoxycarbonylamino, aryloxycarbonylamino, C1-5 alkylcarbamoyloxy, arylcarbamoyloxy, C1-5 alkylsulfonylamino, arylsulfonylamino, C1-5 alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino;
or R6 and R7 together with the carbon they are attached form a carbocyclic ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl or a heterocyclic ring selected from the group consisting of pyrrolidinyl, piperidinyl, hexahydropyridazinyl, hexahydropyrimidinyl, piperazinyl, pyranyl, thiopyranyl, 1,2-thiazinanyl-1,1-dioxide, 1,2,6-thiadiazinanyl-1,1-dioxide, isothiazolidinyl-1,1-dioxide and imidazolidinyl-2,4-dione, the carbocyclic or heterocyclic ring being optionally substituted with one or more Rg;
Rg is selected from the group consisting of alkyl, cycloalkyl, phenyl, heteroaryl selected from the group consisting of furanyl and thienyl, C1-3 alkanoyl, benzoyl, C1-3 alkoxycarbonyl, carbamoyl wherein the nitrogen atom may be independantly mono or disubstituted by C1-5 alkyl, phenyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl and pyridinyl, C1-3 alkylthio wherein the sulfur atom may be oxidised to a sulfoxide or sulfone, phenylthio wherein the sulfur atom may be oxidised to a sulfoxide or sulfone, C1-5 alkylaminosulfonyl, phenylaminosulfonyl, halogen, hydroxy, carboxy and cyano, Rg may be further optionally substituted by one or more Rh;
Rh is selected from the group consisting of C1-3 alkyl, C5-6 cycloalkyl, phenyl optionally substituted by one or more groups selected from halogen, C1-3 alkyl and C1-3 alkoxy, piperidinyl, morpholinyl, piperazinyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, quinolinyl, isoquinolinyl, C1-3 alkoxy, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl, phenyl, heterocyclyl selected from the group consisting of piperidinyl and morpholinyl or heteroaryl selected from the group consisting of furanyl, thienyl and pyridinyl, halogen, hydroxy, oxo and cyano.
R8 is hydrogen, C1-8 alkyl, C3-6 cycloalkyl-alkyl or aryl C1-3 alkyl; and
Ri is hydrogen or C1-5 alkyl.
Even more preferred are compounds of the formula (I) as described immediately above and wherein:
A is as defined above;
R1 is C1-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl and thiopyranyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl or amino wherein R1 is optionally substituted by one or more Ra;
Ra is selected from the group consisting of C1-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, C1-5 alkoxy, aryloxy, C1-5 alkoxycarbonyl, aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, C1-5 alkanoylamino, aroylamino, C1-5 alkylthio, arylthio, ureido wherein either nitrogen atom may be independently substituted by alkyl or aryl, C1-5 alkoxycarbonylamino, aryloxycarbonylamino, C1-5 alkylcarbamoyloxy, arylcarbamoyloxy, C1-5 alkylsulfonylamino, arylsulfonylamino, C1-5 alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may be independently mono or di-substituted by alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy, cyano and nitro, Ra may be further optionally substituted by one or more Rb;
Rb is selected from the group consisting of C1-5 alkyl, C3-6 cycloalkyl, aryl, C1-5 alkoxy, aryloxy, halogen, hydroxy, oxo, carboxy and cyano;
R2 is hydrogen, ORi or methyl;
R3 is hydrogen or methyl;
R4 is hydrogen or methyl;
R5 is C1-5 alkyl, C3-7 cycloalkyl or phenyl wherein R5 is optionally substituted by one or more Rc;
Rc is selected from the group consisting of C1-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, C1-5 alkoxy, aryloxy, aroyl, C1-5 alkoxycarbonyl, aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, C1-5 alkanoylamino, aroylamino, C1-5 alkylthio, arylthio, ureido wherein either nitrogen atom may be independently substituted by C1-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, C1-5 alkoxycarbonylamino, aryloxycarbonylamino, C1-5 alkylcarbamoyloxy, arylcarbamoyloxy, C1-5 alkylsulfonylamino, arylsulfonylamino, C1-5 alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano, Rc may be further optionally substituted by one or more Rd;.
Rd is selected from the group consisting of C1-5 alkyl, C3-6 cycloalkyl, aryl, arylC1-5alkyl, C1-5 alkoxy, aryloxy, arylC1-3alkoxy, aroyl, amino, halogen, hydroxy, oxo, carboxy and cyano;
R6 is hydrogen or C1-5 alkyl said alkyl being optionally interrupted by 1 to two heteroatoms selected from the group consisting of N,O and S;
R7 is hydrogen, C1-5 alkyl said alkyl being optionally interrupted by 1 to two heteroatoms selected from the group consisting of N,O and S, C3-7 cycloalkyl, phenyl, naphthyl or cyano, wherein R7 is optionally substituted by one or more Re;
Re is selected from the group consisting of C1-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, C1-5 alkoxy, aryloxy, arylC1-5alkoxy, heteroarylC1-5alkoxy, C1-5 alkoxycarbonyl, aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl, aryl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, C1-5 alkanoylamino, aroylamino, C1-5 alkylthio, arylthio, arylC1-5 alkylthio, ureido wherein either nitrogen atom may be independently substituted by C1-5 alkyl, aryl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, C1-5 alkoxycarbonylamino, aryloxycarbonylamino, C1-5 alkylcarbamoyloxy, arylcarbamoyloxy, C1-5 alkylsulfonylamino, arylsulfonylamino, C1-5 alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano, Re may be further optionally substituted by one or more Rf;
Rf is selected from the group consisting of C1-5 alkyl, C3-7 cycloalkyl, phenyl optionally substituted by one or more groups selected from halogen, methyl and methoxy, naphthyl optionally substituted by one or more groups selected from halogen, methyl and methoxy, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, C1-5 alkoxy, aryloxy, arylC1-5alkoxy, C1-5 alkoxycarbonyl, aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl, aryl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, C1-5 alkanoylamino, aroylamino, C1-5 alkylthio, arylthio, ureido wherein either nitrogen atom may be independently substituted by C1-5 alkyl, aryl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, C1-5 alkoxycarbonylamino, aryloxycarbonylamino, C1-5 alkylcarbamoyloxy, arylcarbamoyloxy, C1-5 alkylsulfonylamino, arylsulfonylamino, C1-5 alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano;
or R6 and R7 together with the carbon they are attached form a carbocyclic ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl or a heterocyclic ring selected from the group consisting of piperidinyl, hexahydropyridazinyl, hexahydropyrimidinyl, piperazinyl, pyranyl and thiopyranyl, the carbocyclic or heterocyclic ring being optionally substituted with one or more Rg;
Rg is selected from the group consisting of C1-3 alkyl, C3-6 cycloalkyl, C1-3 alkanoyl, benzoyl, C1-3 alkoxycarbonyl, carbamoyl wherein the nitrogen atom may be independantly mono or disubstituted by C1-5 alkyl, phenyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl and pyridinyl, halogen, hydroxy, carboxy and cyano, Rg may be further optionally substituted by one or more Rh;
Rh is selected from the group consisting of methyl, phenyl optionally substituted by one or more groups selected from halogen, methyl and methoxy, piperidinyl, morpholinyl, piperazinyl, pyridinyl, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-3 alkyl, phenyl, heterocyclyl selected from the group consisting of piperidinyl and morpholinyl or heteroaryl selected from the group consisting of furanyl, thienyl and pyridinyl, halogen, hydroxy, oxo and cyano;
R8 is hydrogen, C1-5 alkyl, C5-6 cycloalkyl-C1-3-alkyl or benzyl;
Ri is hydrogen or methyl; and
X is O.
Yet even more preferred are compounds of the formula (I) as described immediately above and wherein:
A is as defined above;
R1 is C1-5 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl, piperazinyl, pyranyl and thiopyranyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl or amino, wherein R1 is optionally substituted by one or more Ra;
Ra is selected from the group consisting of C1-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, C1-3 alkoxy, phenoxy, C1-3 alkoxycarbonyl, aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl, phenyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, C1-5 alkanoylamino, aroylamino, C1-5 alkylthio, arylthio, ureido wherein either nitrogen atom may be independently substituted by C1-5alkyl, phenyl or naphthyl, C1-5 alkoxycarbonylamino, C1-5 alkylcarbamoyloxy, arylcarbamoyloxy, C1-5 alkylsulfonylamino, arylsulfonylamino, C1-5 alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-5alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano, Ra may be further optionally substituted by one or more Rb;
Rb is selected from the group consisting of C1-3 alkyl, C5-6 cycloalkyl, aryl, C1-3 alkoxy, phenoxy, halogen, hydroxy, oxo, carboxy and cyano;
R2 is hydrogen or ORi;
R3 is hydrogen;
R4 is hydrogen;
R5 is C1-5 alkyl, C3-6 cycloalkyl or phenyl, wherein R5 is optionally substituted by one or more Rc;
Rc is selected from the group consisting of C1-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl, heteroaryl selected from the group consisting of furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, quinolinyl and isoquinolinyl, C1-5 alkoxy, phenoxy, aroyl, C1-5 alkoxycarbonyl, aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, C1-5 alkanoylamino, aroylamino, C1-3 alkylthio, phenylthio, ureido wherein either nitrogen atom may be independently substituted by C1-3 alkyl, phenyl or heteroaryl selected the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, C1-5 alkoxycarbonylamino, C1-5 alkylcarbamoyloxy, arylcarbamoyloxy, C1-5 alkylsulfonylamino, arylsulfonylamino, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-3 alkyl, phenyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, halogen, hydroxy, oxo, carboxy and cyano, Rc may be further optionally substituted by one or more Rd;
Rd is selected from the group consisting of C1-5 alkyl, C5-6 cycloalkyl, phenyl, naphthyl, arylC1-3alkyl, C1-5 alkoxy, phenoxy, arylC1-3alkoxy, aroyl, amino, halogen, hydroxy, oxo, carboxy and cyano;
R6 is hydrogen or C1-3alkyl said alkyl being optionally interrupted by 1 to two heteroatoms selected from the group consisting of N,O and S;
R7 is hydrogen, C1-5 alkyl said alkyl being optionally interrupted by 1 to two heteroatoms selected from the group consisting of N,O and S, C3-6 cycloalkyl, phenyl or cyano, wherein R7 is optionally substituted by one or more Re;
Re is selected from the group consisting of C1-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, C1-5 alkoxy, aryloxy, arylC1-3alkoxy, heteroarylC1-3alkoxy, C1-5 alkoxycarbonyl, aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl, phenyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, C1-5 alkanoylamino, aroylamino, C1-3 alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, arylthio, arylC1-3alkylthio, ureido wherein either nitrogen atom may be independently substituted by C1-5 alkyl or phenyl, C1-5 alkoxycarbonylamino, C1-5 alkylsulfonylamino, arylsulfonylamino, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, and indolyl, halogen, hydroxy, oxo, carboxy and cyano, Re may be further optionally substituted by one or more Rf;
Rf is selected from the group consisting of C1-3 alkyl, C5-6 cycloalkyl, phenyl optionally substituted by one or more groups selected from halogen and methyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl and indolyl, C1-5 alkoxy, aryloxy, arylC1-3alkoxy, C1-5 alkoxycarbonyl, aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl or aryl, C1-5 alkanoylamino, aroylamino, C1-5 alkylthio, arylthio, ureido wherein either nitrogen atom may be independently substituted by C1-5 alkyl or aryl, C1-5 alkoxycarbonylamino, aryloxycarbonylamino, C1-5 alkylcarbamoyloxy, arylcarbamoyloxy, C1-5 alkylsulfonylamino, arylsulfonylamino, C1-5 alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl or aryl, halogen, hydroxy, oxo, carboxy and cyano;
or
R6 and R7 together with the carbon they are attached form a carbocyclic ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl or heterocyclic ring selected from the group consisting of piperidinyl, morpholinyl and thiomorpholinyl, the carbocyclic or heterocyclic ring being optionally substituted with one or more Rg;
Rg is selected from the group consisting of C1-3 alkyl, C3-6 cycloalkyl, C1-3 alkanoyl, C1-3 alkoxycarbonyl and carbamoyl wherein the nitrogen atom may be independantly mono or disubstituted by C1-5 alkyl; Rg may be further optionally substituted by one or more Rh;
Rh is phenyl or amino wherein the nitrogen atom may be independently mono or di-substituted by C1-3 alkyl;
R8 is hydrogen or methyl;
Ri is hydrogen or methyl and
and X is O.
Still yet even more preferred are compounds of the formula (I) as described immediately above and wherein:
A is as defined above;
R1 is C1-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl, piperazinyl, pyranyl and thiopyranyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl or amino, wherein R1 is optionally substituted by one or more Ra;
Ra is selected from the group consisting of C1-3 alkyl, C5-6 cycloalkyl, phenyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, C1-3 alkoxy, C1-3 alkoxycarbonyl, aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-3 alkyl, phenyl or heteroaryl selected from the group consisting of pyrrolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl and benzthiazolyl, C1-5 alkanoylamino, aroylamino, C1-3 alkylthio, arylthio, ureido wherein either nitrogen atom may be independently substituted by C1-3alkyl or phenyl, C1-5 alkylsulfonylamino, arylsulfonylamino, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-3alkyl, phenyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of pyrrolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano, Ra may be further optionally substituted by one or more Rb;
Rb is selected from the group consisting of C1-3 alkyl, C5-6 cycloalkyl, C1-3 alkoxy, halogen and hydroxy;
R2 is hydrogen;
R3 and R4 are as defined immediately above;
R5 is C1-5 alkyl, C5-6 cycloalkyl or phenyl wherein R5 is optionally substituted by one or more Rc;
Rc is selected from the group consisting of C1-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, 4-piperidinyl, 4-morpholinyl, piperazinyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, C1-5 alkoxy, phenoxy, aroyl, C1-5 alkoxycarbonyl, aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl or phenyl, C1-5 alkanoylamino, C1-3 alkylthio, ureido wherein either nitrogen atom may be independently substituted by C1-3 alkyl or phenyl, C1-5 alkoxycarbonylamino, C1-5 alkylsulfonylamino, arylsulfonylamino, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-3 alkyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano, Rc may be further optionally substituted by one or more Rd;
Rd is selected from the group consisting of C1-5 alkyl, C5-6 cycloalkyl, phenyl, benzyl, C1-5 alkoxy, phenoxy, benzyloxy, aroyl, halogen, hydroxy, oxo, carboxy and cyano;
R6 is hydrogen or C1-3alkyl said alkyl being optionally interrupted by 1 to two heteroatoms selected from the group consisting of N,O and S;
R7 is hydrogen, C1-5 alkyl said alkyl being optionally interrupted by 1 to two heteroatoms selected from the group consisting of N,O and S, phenyl or cyano, wherein R7 is optionally substituted by one or more Re;
Re is selected from the group consisting of C1-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, C1-3 alkoxy, benzyloxy, pyridylC1-3alkoxy, thienylC1-3alkoxy, furanylC1-3alkoxy, C1-3 alkoxycarbonyl, phenoxyoxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-3 alkyl or phenyl, C1-5 alkanoylamino, aroylamino, methylthio, benzylthio, ureido wherein either nitrogen atom may be independently substituted by C1-5 alkyl or phenyl, C1-3 alkoxycarbonylamino, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano, Re may be further optionally substituted by one or more Rf;
Rf is selected from the group consisting of C1-3 alkyl, phenyl optionally substituted by one or more groups selected from the group consisting of halogen and methyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl and pyridinyl, C1-3 alkoxy, aryloxy, benzyloxy, C1-5 alkoxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl or phenyl, C1-5 alkanoylamino, aroylamino, C1-5 alkylthio, ureido wherein either nitrogen atom may be independently substituted by C1-5 alkyl or phenyl, C1-5 alkoxycarbonylamino, C1-5 alkylcarbamoyloxy, arylcarbamoyloxy, C1-3 alkylsulfonylamino, arylsulfonylamino, C1-3 alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-3 alkyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano;
or R6 and R7 together with the carbon they are attached form cyclopropyl or a heterocyclic ring selected from the group consisting of piperidinyl, pyranyl and thiopyranyl, the cyclopropyl or heterocyclic ring being optionally substituted with one or more Rg;
Rg is selected from the group consisting of methyl, benzyl, acetyl, benzoyl, benzyloxycarbonyl and ethoxycarbonyl;
R8 is hydrogen and
X is O.
Even much more preferred are compounds of the formula (I) as described immediately above and wherein:
A is as described above;
R1 is C3-6 cycloalkyl, phenyl, naphthyl, piperidinyl, morpholinyl, piperazinyl, pyranyl, thiopyranyl, furanyl, thienyl, pyrrolyl or amino, wherein R1 is optionally substituted by one or more Ra;
Ra is selected from the group consisting of C1-3 alkyl, C5-6 cycloalkyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, C1-3 alkoxy, C1-3 alkoxycarbonyl, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-3 alkyl or phenyl, C1-5 alkanoylamino, aroylamino, ureido wherein either nitrogen atom may be independently substituted by C1-3alkyl or phenyl, C1-5 alkylsulfonylamino, arylsulfonylamino, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-3alkyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano, Ra may be further optionally substituted by one or more Rb;
Rb is selected from the group consisting of C1-3alkyl, C1-3alkoxy, halogen and hydroxy;
R2,R3 and R4 are as defined immediately above;
R5 is C1-5 alkyl, C5-6 cycloalkyl or phenyl, wherein R5 is optionally substituted by one or more groups of the formula Rc;
Rc is selected from the group consisting of C1-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, 4-piperidinyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, C1-3 alkoxy, C1-5 alkoxycarbonyl, C1-5 alkanoyloxy, benzoyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-3 alkyl or phenyl, C1-5 alkanoylamino, C1-3 alkylthio, C1-3 alkoxycarbonylamino, C1-3 alkylsulfonylamino, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-3 alkyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano, Rc may be further optionally substituted by one or more Rd;
Rd is selected from the group consisting of C1-3 alkyl, phenyl, benzyl, C1-3 alkoxy, phenoxy, benzyloxy, benzoyl, halogen, hydroxy, oxo, carboxy and cyano;
wherein the configuration at the stereocenter defined by R4 and R5 and the carbon they are attached to is defined as L;
R6 is hydrogen or C1-2 alkyl said alkyl being optionally interrupted by 1 to two heteroatoms selected from the group consisting of N,O and S;
R7 is C1-5 alkyl said alkyl being optionally interrupted by 1 to two heteroatoms selected from the group consisting of N,O and S; phenyl or cyano wherein R7 is optionally substituted by one or more groups of the formula Re;
Re is selected from the group consisting of methyl, C3-6 cycloalkyl, phenyl, naphthyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, C1-3 alkoxy, benzyloxy, pyridylC1-3alkoxy, thienylC1-3alkoxy, furanylC1-3alkoxy, C1-5 alkanoylamino, aroylamino, methylthio, benzylthio, C1-3 alkoxycarbonylamino, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano, Re may be further optionally substituted by one or more Rf;.
Rf is selected from the group consisting of C1-3 alkyl, phenyl optionally substituted by one or more groups selected from halogen and methyl, C1-3 alkoxy, aryloxy, benzyloxy, C1-3 alkoxycarbonyl, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-3 alkyl or phenyl, C1-5 alkanoylamino, aroylamino, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-3 alkyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano;
or R6 and R7 together with the carbon they are attached form cyclopropyl or a heterocyclic ring selected from the group consisting of piperidinyl and pyranyl, the cyclopropyl or heterocyclic ring being optionally substituted with one or more Rg.
Rg is methyl;
Rh is as described immediately above; and
X is O.
Yet even much more preferred are compounds of the formula (I) as described immediately above and wherein:
A is as described above;
R1 is cyclopropyl, cyclohexyl, phenyl, naphthyl, piperidinyl, morpholinyl, piperazinyl, pyranyl, thiopyranyl or amino wherein R1 is optionally substituted by one or more Ra;
Ra is selected from the group consisting of C1-3 alkyl, C5-6 cycloalkyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, C1-3 alkoxy, C1-3 alkoxycarbonyl, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-3 alkyl or phenyl, C1-5 alkanoylamino, aroylamino, C1-5 alkylsulfonylamino, arylsulfonylamino, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-3 alkyl, halogen, hydroxy, oxo, carboxy and cyano, Ra may be further optionally substituted by one or more Rb;
Rb is selected from the group consisting of C1-3 alkoxy, halogen and hydroxy,
R2,R3 and R4 are as described immediately above;
R5 is C1-5 alkyl or C5-6 cycloalkyl wherein R5 is optionally substituted by one or more Rc;
Rc is selected from the group consisting of methyl, C3-6 cycloalkyl, phenyl, naphthyl, thienyl, imidazolyl, pyridinyl, indolyl, C1-4 alkoxy, C1-5 alkanoylamino, methylthio, halogen, hydroxy, oxo, carboxy and cyano, Rc may be further optionally substituted by one or more Rd;
Rd is selected from the group consisting of methyl, phenyl, benzyl, methoxy, phenoxy, benzyloxy, benzoyl, halogen and hydroxy;
R6 is as described immediately above;
R7 is C1-5 alkyl or phenyl, wherein R7 is optionally substituted by one or more Re;
Re is selected from the group consisting of C3-6 cycloalkyl, phenyl, naphthyl, thienyl, imidazolyl, pyridinyl, indolyl, methoxy, benzyloxy, C1-3 alkanoylamino, methylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, benzylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, methoxycarbonylamino, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-3 alkyl, halogen, hydroxy, carboxy and cyano, Re may be further optionally substituted by one or more Rf;
Rf is selected from the group consisting of methyl, phenyl optionally substituted by one or more groups selected from halogen or methyl, methoxy, phenoxy, benzyloxy, methoxycarbonyl, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-3 alkyl or phenyl, halogen, hydroxy and carboxy;
or R6 and R7 together with the carbon they are attached form a cyclopropyl ring; and
Rg, Rh and X are as described immediately above.
Penultimately preferred are compounds of the formula (I) as described immediately above and wherein:
A is as described above;
R1 is-cyclopropyl, cyclohexyl, phenyl, naphthyl, piperidinyl, morpholinyl, piperazinyl, pyranyl or thiopyranyl, wherein R1 is optionally substituted by one or more Ra;
Ra is selected from the group consisting of pyrrolyl, imidazolyl, indolyl, benzimidazolyl, methoxy, methoxycarbonyl, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-3 alkyl, halogen, hydroxy and carboxy, Ra may be further optionally substituted by one or more Rb;
Rb is selected from the group consisting of methoxy, halogen and hydroxy;
R2,R3,R4 and R5 are as described immediately above;
Rc is selected from the group consisting of methyl, C3-6 cycloalkyl, phenyl, naphthyl, C1-4 alkoxy, C1-3 alkanoylamino, methylthio, halogen, hydroxy, oxo, carboxy and cyano, Rc may be further optionally substituted by one or more Rd;
Rd is selected from the group consisting of methyl, phenyl, methoxy, halogen and hydroxy;
R6 is hydrogen;
R7 is as described immediately above;
Re is selected from the group consisting of C5-6 cycloalkyl, phenyl, naphthyl, thienyl, indolyl, methoxy, benzyloxy, methylthio, benzylthio, methoxycarbonylamino, halogen, hydroxy, carboxy and cyano, Re may be further optionally substituted by one or more Rf;
Rf is selected from the group consisting of methyl, phenyl optionally substituted by halogen, methoxy, phenoxy, benzyloxy, methoxycarbonyl, halogen, hydroxy and carboxy; and
Rg, Rh and X are as described immediately above.
Ultimately preferred are compounds of the formula(I) wherein:
A is as described above;
R1 is 4-morpholinyl, 4-pyranyl or phenyl;
R2,R3,R4, Ra and Rb are as described immediately above;
R5 is C1-5 alkyl wherein R5 is optionally substituted by one or more Rc;
Rc is selected from the group consisting of C3-6 cycloalkyl, phenyl and 2-naphthyl, Rc may be further optionally substituted by one or more Rd;
Rd is selected from the group consisting of methyl and halogen,
R6 and R7 are as described immediately above;
Re is selected from the group consisting of C5-6 cycloalkyl, phenyl, naphthyl, indolyl, benzyloxy, methylthio, benzylthiohalogen and carboxy, Re may be further optionally substituted by one or more Rf; and
Rf is selected from the group consisting of methyl, methoxy, methoxycarbonyl, halogen and hydroxy; and
Rg, Rh and X are as described immediately above.
In a second generic aspect of the invention, there are provided compounds of formula (Ia): 
wherein:
A is xe2x80x94C(O)xe2x80x94 or xe2x80x94CH(OR8)xe2x80x94;
R1 is alkyl, alkoxy, cycloalkyl, aryl, aryloxy, benzyloxy, heterocyclyl, heteroaryl or amino wherein R1 is optionally substituted by one or more Ra;
Ra is selected from the group consisting of a bond, alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, aryloxy, alkanoyl, aroyl, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by alkyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, arylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, ureido wherein either nitrogen atom may be independently substituted by alkyl, aryl, heterocyclyl or heteroaryl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, arylsulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may be independently mono or di-substituted by alkyl, aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; Ra may be further optionally substituted by one or more Rb;
Rb is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, arylalkyl, alkoxy, aryloxy, arylalkoxy, alkanoyl, aroyl, amino wherein the nitrogen atom may be independently mono or di-substituted by alkyl, aryl, acyl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino;
R2 is hydrogen, ORj or lower alkyl;
R3 is hydrogen or lower alkyl;
R4 is hydrogen or lower alkyl;
R5 is hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein R5 is optionally substituted by one or more Rc;
Rc is selected from the group consisting of a bond, alkyl, cycloalkyl, bicycloalkyl, aryl, indenyl, indanyl, dihydronaphthyl, tetrahydronaphthyl, heterocyclyl, heteroaryl, alkoxy, aryloxy, arylalkoxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyl, aroyl, alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by alkyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, arylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, ureido wherein either nitrogen atom may be independently substituted by alkyl, aryl, heterocyclyl or heteroaryl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, arylsulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may be independently mono or di-substituted by alkyl, aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rc may be further optionally substituted by one or more Rd;
Rd is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkyl, alkoxy, aryloxy, arylalkoxy, alkanoyl, aroyl, amino, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino;
or R4 and R5 together with the carbon they are attached form a 3 to 7 membered carbocyclic ring optionally substituted with one or more Rd;
R6 is hydrogen or lower alkyl wherein one or more carbon atoms are optionally replaced by 1 to two heteroatoms selected from the group consisting of N,O and S;
R7 is hydrogen, alkyl wherein one or more carbon atoms are optionally replaced by 1 to two heteroatoms selected from the group consisting of N,O and S, cycloalkyl, aryl, heterocyclyl, heteroaryl or cyano, wherein R7 is optionally substituted by one or more Re;
Re is selected from the group consisting of a bond alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, aryloxy, arylalkoxy, alkanoyl, aroyl, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy, heteroarylalkoxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by alkyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylcarbamoyl, arylcarbamoyl, alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, arylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, arylalkylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, ureido wherein either nitrogen atom may be independently substituted by alkyl, aryl, heterocyclyl or heteroaryl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, arylsulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may be independently mono or di-substituted by alkyl, aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Re may be further optionally substituted by one or more Rf;
Rf is selected from the group consisting of alkyl, cycloalkyl, aryl optionally substituted by one or more groups selected from halogen, methyl or methoxy, heterocyclyl, heteroaryl, alkoxy, aryloxy, arylalkoxy, alkoxycarbonyl, aryloxycarbonyl, alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by alkyl, aryl, heterocyclyl or heteroaryl, alkanoylamino, aroylamino, alkylcarbamoyl, arylcarbamoyl, alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, arylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, ureido wherein either nitrogen atom may be independently substituted by alkyl, aryl, heterocyclyl or heteroaryl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, arylsulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may be independently mono or di-substituted by alkyl, aryl, heterocyclyl or heteroaryl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino;
or R6 and R7 together with the carbon they are attached form a 3 to 7 membered carbocyclic or heterocyclic ring, the carbocyclic or heterocyclic ring being optionally substituted with one or more Rg;
Rg is selected from the group consisting of a bond, alkyl, cycloalkyl, bicycloalkyl, benzyl, aryl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, indolinyl and piperazinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrimidinyl, pyrrolyl, imidazolyl and pyridinyl, C1-5 alkanoyl, aroyl, C1-5 alkoxycarbonyl, aryloxycarbonyl, carbamoyl wherein the nitrogen atom may be independantly mono or disubstituted by C1-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, is thienyl, pyrrolyl, thiazolyl, imidazolyl, pyridinyl, benzimidazolyl and quinolinyl, C1-5 alkanoylamino, aroylamino, C1-5 alkylthio, arylthio, C1-5 alkylsulfonylamino, arylsulfonylamino, C1-5 alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may be independently mono or disubstituted by alkyl, cycloalkyl, bicycloalkyl, aryl, aroyl, benzoyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rg may be further optionally substituted by one or more Rh;
Rh is selected from the group consisting of a bond, C1-5 alkyl, C3-7 cycloalkyl, aryl optionally substituted by one or more groups selected from halogen, lower alkyl or lower alkoxy, benzyl, benzyloxy, dihydronaphthyl, tertrahydronaphthyl, indenyl, indanyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, tetrahydropyranyl and tetrahydrothiopyranyl, heteroaryl selected from the group consisting of furanyl, thienyl pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, benzoxazolyl and quinoxalinyl, C1-5 alkoxy, aryloxy, amino wherein the nitrogen atom may be independently mono or di-substituted by alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl and morpholinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl and pyridinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino; Rh may be further optionally substituted by one or more Ri;
Ri is alkyl, hydroxy, oxo and halogen;
Rj is hydrogen, alkyl, cycloalkyl;
R8 is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl or arylalkyl;
X is O or S; and
pharmaceutically acceptable salts, esters or tautomers thereof.
Preferred are compounds of the formula (Ia) wherein:
R1 is C1-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 2-oxa-5-aza-bicyclo[2,2,1]heptanyl, piperazinyl, indolinyl, tetrahydropyranyl and tetrahydrothiopyranyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl and amino wherein R1 is optionally substituted by one or more Ra;
Ra is selected from the group consisting of a bond, C1-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, C1-8 alkoxy, aryloxy, C1-8 alkoxycarbonyl, aryloxycarbonyl, C1-8 alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-8 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, C1-8 alkanoylamino, aroylamino, C1-8 alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, arylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, ureido wherein either nitrogen atom may be independently substituted by alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, arylsulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may be independently mono or di-substituted by alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino, guanidino; Ra may be further optionally substituted by one or more Rb;
Rb is selected from the group consisting of C1-8 alkyl, C3-6 cycloalkyl, aryl, heteroaryl, C1-8 alkoxy, aryloxy, alkanoyl, aroyl, amino wherein the nitrogen atom may be independently mono or di-substituted by alkyl, cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino;
R2 is hydrogen, ORj or C1-3 alkyl;
R3 is hydrogen or C1-5 alkyl;
R4 is hydrogen or C1-5 alkyl;
R5 is hydrogen, C1-8 alkyl, C3-7 cycloalkyl, aryl wherein R5 is optionally substituted by one or more Rc;
Rc is selected from the group consisting of a bond, C1-8 alkyl, C3-7 cycloalkyl, bicycloalkyl, aryl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, C1-8 alkoxy, aryloxy, alkanoyl, aroyl, C1-8 alkoxycarbonyl, aryloxycarbonyl, C1-8 alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-8 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, C1-8 alkanoylamino, aroylamino, C1-8 alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, arylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, ureido wherein either nitrogen atom may be independently substituted by alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxycarbonylamino, C1-5aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, arylsulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may be independently mono or di-substituted by alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Rc may be further optionally substituted by one or more Rd;
Rd is selected from the group consisting of C1-8 alkyl, C3-6 cycloalkyl, aryl, arylalkyl, C1-8 alkoxy, aryloxy, arylalkoxy, aroyl, amino, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino;
R7 is hydrogen, C1-8 alkyl wherein one or more carbon atoms are optionally replaced by 1 to two heteroatoms selected from the group consisting of N,O and S, C3-7 cycloalkyl, aryl, heteroaryl or cyano, wherein R7 is optionally substituted by one or more Re;
Re is selected from the group consisting of a bond, C1-8 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, C1-8 alkoxy, aryloxy, arylC1-8alkoxy, heteroarylC1-8alkoxy wherein the heteroaryl is as hereinabove described in this paragraph, C1-8 alkoxycarbonyl, aryloxycarbonyl, C1-8 alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-8 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, C1-8 alkanoylamino, aroylamino, C1-8 alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, arylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, arylC1-8 alkylthio, ureido wherein either nitrogen atom may be independently substituted by alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, arylsulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may be independently mono or di-substituted by alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino and guanidino, Re may be further optionally substituted by one or more Rf;
Rf is selected from the group consisting C1-8 alkyl, C3-7 cycloalkyl, aryl optionally substituted by one or more groups selected from the group consisting halogen, methyl and methoxy, heterocyclyl selected from the group consisting pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, C1-8 alkoxy, aryloxy, arylC1-8alkoxy, C1-8 alkoxycarbonyl, aryloxycarbonyl, C1-8 alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-8 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, C1-8 alkanoylamino, aroylamino, C1-8 alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, arylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, ureido wherein either nitrogen atom may be independently substituted by alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, alkoxycarbonylamino, aryloxycarbonylamino, alkylcarbamoyloxy, arylcarbamoyloxy, alkylsulfonylamino, arylsulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may be independently mono or di-substituted by alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and indolinyl, or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenothiazinyl and phenoxazinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino, and guanidino;
or R6 and R7 together with the carbon they are attached form a 3 to 7 membered carbocyclic or heterocyclic ring, the carbocyclic or heterocyclic ring being optionally substituted with one or more Rg;
Rg is selected from the group consisting of a bond, alkyl, cycloalkyl, bicycloalkyl, phenyl, naphthyl, benzyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, indolinyl and piperazinyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrimidinyl and pyridinyl, C1-5alkanoyl, aroyl, C1-5alkoxycarbonyl, aryloxycarbonyl, carbamoyl wherein the nitrogen atom may be independantly mono or disubstituted by C1-5 alkyl, aryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, thiazolyl, imidazolyl, pyridinyl, benzimidazolyl and quinolinyl, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl, C3-6 cycloalkyl, C7-8 bicycloalkyl, phenyl, benzyl, benzoyl or naphthoyl, C1-5 alkylthio wherein the sulfur atom may be oxidised to a sulfoxide or sulfone, arylthio wherein the sulfur atom may be oxidised to a sulfoxide or sulfone, C1-5 alkylaminosulfonyl, arylaminosulfonyl, halogen, hydroxy, oxo, carboxy and cyano, Rg may be further optionally substituted by one or more Rh;
Rh is selected from the group consisting of C1-5 alkyl, C3-7 cycloalkyl, aryl optionally substituted by one or more groups selected from halogen, C1-5 alkyl or C1-5 alkoxy, dihydronaphthyl, tertrahydronaphthyl, indenyl, indanyl, benzyl, benzyloxy, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, tetrahydropyranyl and tetrahydrothiopyranyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, benzoxazolyl and quinoxalinyl, C1-5 alkoxy, aryloxy, amino wherein the nitrogen atom may be independently mono or di-substituted by alkyl, aryl, heterocyclyl selected from the group consisting of piperidinyl and morpholinyl, or heteroaryl selected from the group consisting of furanyl, thienyl and pyridinyl, halogen, hydroxy, oxo, carboxy and cyano; and
R8 is hydrogen, alkyl, cycloalkyl-alkyl or arylalkyl;
Ri is C1-8 alkyl, hydroxy, oxo and halogen
Rj is hydrogen or alkyl and
X is O.
More preferred are compounds of the formula (I) as described immediately above and wherein:
A is xe2x80x94C(O)xe2x80x94;
R1 is C1-5 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 2-oxa-5-aza-bicyclo[2,2,1]heptanyl, piperazinyl, tetrahydropyranyl and tetrahydrothiopyranyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl or amino, wherein R1 is optionally substituted by one or more Ra;
Ra is selected from the group consisting of a bond, C1-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, C1-3 alkoxy, phenoxy, C1-3 alkoxycarbonyl, aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl, phenyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, C1-5 alkanoylamino, aroylamino, C1-5 alkylthio, arylthio, ureido wherein either nitrogen atom may be independently substituted by C1-5alkyl, phenyl or naphthyl; C1-5 alkoxycarbonylamino, C1-5 alkylcarbamoyloxy, arylcarbamoyloxy, C1-5 alkylsulfonylamino, arylsulfonylamino, C1-5 alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-5alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl; thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, halogen, hydroxy, oxo, carboxy and cyano, Ra may be further optionally substituted by one or more Rb;
Rb is selected from the group consisting of C1-3 alkyl, C5-6 cycloalkyl, aryl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, C1-3 alkoxy, phenoxy, C1-8 alkanoyl, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-5alkyl, C3-6 cycloalkyl, phenyl or naphthyl, halogen, hydroxy, oxo, carboxy and cyano;
R2 is hydrogen;
R3 is hydrogen;
R4 is hydrogen;
R5 is C1-5 alkyl, C3-6 cycloalkyl or phenyl, wherein R5 is optionally substituted by one or more Rc;
Rc is selected from the group consisting of a bond, C1-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, indenyl, indanyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl, heteroaryl selected from the group consisting of furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, quinolinyl and isoquinolinyl, C1-5 alkoxy, phenoxy, aroyl, C1-5 alkoxycarbonyl, aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, C1-5 alkanoylamino, aroylamino, C1-3 alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, phenylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, ureido wherein either nitrogen atom may be independently substituted by C1-3 alkyl, phenyl or heteroaryl selected the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, C1-5 alkoxycarbonylamino, C1-5 alkylcarbamoyloxy, arylcarbamoyloxy, C1-5 alkylsulfonylamino, arylsulfonylamino, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-3 alkyl, phenyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, halogen, hydroxy, oxo, carboxy and cyano, Rc may be further optionally substituted by one or more Rd;
Rd is selected from the group consisting of C1-5 alkyl, C5-6 cycloalkyl, phenyl, naphthyl, arylC1-3alkyl, C1-5 alkoxy, phenoxy, arylC1-3alkoxy, aroyl, amino, halogen, hydroxy, oxo, carboxy and cyano;
R6 is hydrogen or C1-3alkyl wherein one or more carbon atoms are optionally replaced by 1 to two heteroatoms selected from the group consisting of N,O and S;
R7 is hydrogen, C1-5 alkyl wherein one or more carbon atoms are optionally replaced by 1 to two heteroatoms selected from the group consisting of N,O and S, C3-6 cycloalkyl, phenyl, naphthyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl or cyano, wherein R7 is optionally substituted by one or more Re;
Re is selected from the group consisting of C1-3 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl, C1-5 alkoxy, aryloxy, arylC1-3alkoxy, heteroarylC1-3alkoxy wherein the heteroaryl is as hereinabove described in this paragraph, C1-5 alkoxycarbonyl, aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl, phenylor heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl and indolyl, C1-5 alkanoylamino, aroylamino, C1-3 alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, arylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, arylC1-3alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, ureido wherein either nitrogen atom may be independently substituted by C1-5 alkyl or phenyl, C1-5 alkoxycarbonylamino, C1-5 alkylsulfonylamino, arylsulfonylamino, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl, phenyl, naphthyl, heterocyclyl selected from the group consisting of piperidinyl, morpholinyl and piperazinyl or heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl and pyridinyl, indolyl, halogen, hydroxy, oxo, carboxy and cyano, Re may be further optionally substituted by one or more Rf;
Rf is selected from the group consisting of C1-5 alkyl, C3-6 cycloalkyl, phenyl optionally substituted by one or more groups selected from halogen or methyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl and indolyl, C1-5 alkoxy, aryloxy, arylC1-3alkoxy, C1-5 alkoxycarbonyl, aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl or aryl, C1-5 alkanoylamino, aroylamino, C1-5 alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, arylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, ureido wherein either nitrogen atom may be independently substituted by C1-5 alkyl or aryl, C1-5 alkoxycarbonylamino, aryloxycarbonylamino, C1-5 alkylcarbamoyloxy, arylcarbamoyloxy, C1-5 alkylsulfonylamino, arylsulfonylamino, C1-5 alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl or aryl, halogen, hydroxy, oxo, carboxy and cyano;
or
R6 and R7 together with the carbon they are attached form a carbocyclic ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or heterocyclic ring selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl and tetrahydrothiopyranyl, the carbocyclic or heterocyclic ring being optionally substituted with one or more Rg;
Rg is selected from the group consisting of a bond, C1-8 alkyl, C3-8 cycloalkyl, C7-8 bicycloalkyl, benzyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl and morpholinyl, heteroaryl selected from the group consisting of thienyl, pyrimidinyl and pyridinyl, C1-5 alkanoyl, C1-3 alkoxycarbonyl, carbamoyl wherein the nitrogen atom may be independantly mono or disubstituted by C1-5 alkyl and amino wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl, C3-6 cycloalkyl, C7-8 bicycloalkyl, phenyl, benzyl, benzoyl or naphthoyl, Rg may be further optionally substituted by one or more Rh; and
Rh is selected from the group consisting of C1-8 alkyl, C3-8 cycloalkyl, phenyl, benzyl, benzyloxy, heterocyclyl selected from the group consisting of piperidinyl, indolinyl, tetrahydropyranyl and tetrahydrothiopyranyl, heteroaryl selected from the group consisting of thienyl, pyrrolyl, pyridinyl, pyrimidinyl, indolyl, benzimidazolyl, quinolinyl and isoquinolinyl, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-3 alkyl, halogen, hydroxy, oxo, cyano and trifluoromethyl.
Even more preferred are compounds of the formula (Ia) as described immediately above and wherein:
R1 is C3-6 cycloalkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydropyranyl, furanyl, thienyl, pyrrolyl or amino, wherein R1 is optionally substituted by one or more Ra;
Ra is selected from the group consisting of a bond, C1-3 alkyl, C5-6 cycloalkyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, C1-3 alkoxy, C1-3 alkoxycarbonyl, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-3 alkyl or phenyl; C1-5alkoxycarbonylamino, C1-5 alkanoylamino, aroylamino, ureido wherein either nitrogen atom may be independently substituted by C1-3alkyl or phenyl;, C1-5 alkylsulfonylamino, arylsulfonylamino, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-3alkyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano, Ra may be further optionally substituted by one or more Rb;
Rb is selected from the group consisting of C1-3alkyl, C1-3alkoxy, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-3alkyl or phenyl halogen, oxo and hydroxy;
R5 is C1-5 alkyl, C3-6 cycloalkyl or phenyl, wherein R5 is optionally substituted by one or more groups of the formula Rc;
Rc is selected from the group consisting of a bond, C1-3 alkyl, C3-6 cycloalkyl, C7-8 bicycloalkyl, phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, 4-piperidinyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, indolyl, C1-3 alkoxy, C1-5 alkoxycarbonyl, C1-5 alkanoyloxy, benzoyloxy, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-3 alkyl or phenyl, C1-5 alkanoylamino, C1-3 alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, C1-3 alkoxycarbonylamino, C1-3 alkylsulfonylamino, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-3 alkyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano, Rc may be further optionally substituted by one or more Rd;
Rd is selected from the group consisting of C1-3 alkyl, phenyl, benzyl, C1-3 alkoxy, phenoxy, benzyloxy, benzoyl, halogen, hydroxy, oxo, carboxy and cyano;
wherein the configuration at the stereocenter defined by R4 and R5 and the carbon they are attached to is defined as L;
R6 is hydrogen or C1-2alkyl one or more carbon atoms are optionally replaced by 1 to two heteroatoms selected from the group consisting of N,O and S;
R7 is C1-5 alkyl said alkyl being optionally interrupted by 1 to two heteroatoms selected from the group consisting of N,O and S; phenyl, pyridinyl or cyano wherein R7 is optionally substituted by one or more groups of the formula Re;
Re is selected from the group consisting of a bond, methyl, C3-6 cycloalkyl, phenyl, naphthyl, furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, pyrrolidinyl, piperidinyl, indolyl, C1-3 alkoxy, benzyloxy, pyridinylC1-3alkoxy, thienylC1-3alkoxy, furanylC1-3alkoxy, C1-5 alkanoylamino, aroylamino, methylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, benzylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, C1-3 alkoxycarbonylamino, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano, Re may be further optionally substituted by one or more Rf;.
Rf is selected from the group consisting of C1-5 alkyl, C3-6 cycloalkyl, phenyl optionally substituted by one or more groups selected from halogen or methyl, C1-3 alkoxy, aryloxy, benzyloxy, C1-3 alkoxycarbonyl, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-3 alkyl or phenyl, C1-5 alkanoylamino, aroylamino, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-3 alkyl or phenyl, halogen, hydroxy, oxo, carboxy and cyano;
R6 and R7 together with the carbon they are attached form a carbocyclic ring selected from the group consisting of cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl or heterocyclic ring selected from the group consisting of pyrrolidinyl, piperidinyl and tetrahydropyranyl, the carbocyclic or heterocyclic ring being optionally substituted with one or more Rg;
Rg is selected from the group consisting of a bond C1-8 alkyl, C3-8 cycloalkyl, C7-8 bicycloalkyl, benzyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, heterocyclyl selected from the group consisting of piperidinyl, tetrahydropyranyl, and tetrahydrothiopyranyl, C1-5 alkanoyl, C1-3 alkoxycarbonyl, carbamoyl wherein the nitrogen atom may be independantly mono or disubstituted by C1-5 alkyl and amino wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl, C3-6 cycloalkyl, C7-8 bicycloalkyl, phenyl, benzyl, benzoyl or naphthoyl, Rg may be further optionally substituted by one or more Rh; and
Rh is selected from the group consisting of C1-8 alkyl, C3-8 cycloalkyl, phenyl, benzyl, benzyloxy, heterocyclyl selected from the group consisting of piperidinyl, indolinyl, tetrahydropyranyl and tetrahydrothiopyranyl, heteroaryl selected from the group consisting of thienyl, pyridinyl, indolyl, pyrrolyl and benzimidazolyl, amino wherein the nitrogen atom may be independently mono or di-substituted by methyl, halogen, hydroxy, oxo, cyano and trifluoromethyl.
Yet even more preferred are compounds of the formula (Ia) as described immediately above and wherein:
R1 is cyclohexyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or amino wherein R1 is optionally substituted by one or more Ra;
Ra is selected from the group consisting of a bond, C1-3 alkyl, C5-6 cycloalkyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, C1-3 alkoxy, C1-3 alkoxycarbonyl, carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-3 alkyl or phenyl, C1-5alkoxycarbonylamino, C1-5 alkanoylamino, aroylamino, C1-5 alkylsulfonylamino, arylsulfonylamino, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-3 alkyl, halogen, hydroxy, oxo, carboxy and cyano, Ra may be further optionally substituted by one or more Rb;
Rb is selected from the group consisting of C1-3 alkoxy, halogen and hydroxy,
R5 is C1-5 alkyl wherein R5 is optionally substituted by one or more Rc;
Rc is selected from the group consisting of a bond, C3-6 cycloalkyl, C7-8 bicycloalkyl, phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, thienyl, imidazolyl, pyridinyl, indolyl, C1-3 alkoxy, C1-5 alkanoylamino, methylthio, halogen, hydroxy, oxo, carboxy and cyano, Rc may be further optionally substituted by one or more Rd;
Rd is selected from the group consisting of C1-3 alkyl, phenyl, benzyl, methoxy, phenoxy, benzyloxy, benzoyl, halogen and hydroxy;
R7 is C1-5 alkyl or phenyl, wherein R7 is optionally substituted by one or more Re;
Re is selected from the group consisting of a bond, C3-6 cycloalkyl, phenyl, naphthyl, thienyl, imidazolyl, pyrrolidinyl, piperidinyl, pyridinyl, indolyl, C1-5 alkoxy, benzyloxy, C1-3 alkanoylamino, methylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, benzylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, methoxycarbonylamino, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl, halogen, hydroxy, carboxy and cyano, Re may be further optionally substituted by one or more Rf;
Rf is selected from the group consisting of C1-5 alkyl, C3-6 cycloalkyl, phenyl optionally substituted by one or more groups selected from halogen or methyl, methoxy, phenoxy, benzyloxy, methoxycarbonyl, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-3 alkyl or phenyl, halogen, hydroxy and carboxy;
R6 and R7 together with the carbon they are attached form a carbocyclic ring selected from the group consisting of cyclopropyl and cyclohexyl or heterocyclic ring selected from the group consisting of pyrrolidinyl and piperidinyl, the carbocyclic or heterocyclic ring being optionally substituted with one or more Rg;
Rg is selected from the group consisting of a bond, C1-8 alkyl, C3-8 cycloalkyl, C7-8 bicycloalkyl, benzyl, tetrahydronaphthyl, indanyl, heterocyclyl selected from the group consisting of tetrahydropyranyl and tetrahydrothiopyranyl, acetyl, methoxycarbonyl, carbamoyl wherein the nitrogen atom may be independantly mono or disubstituted by C1-3 alkyl and amino wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl, C3-6 cycloalkyl, benzyl or benzoyl, Rg may be further optionally substituted by one or more Rh; and
Rh is selected from the group consisting of C1-8 alkyl, C3-7 cycloalkyl, phenyl, benzyl, benzyloxy, heterocyclyl selected from the group consisting of piperidinyl, tetrahydropyranyl and tetrahydrothiopyranyl, heteroaryl selected from the group consisting of thienyl, pyridinyl, indolyl and benzimidazolyl, amino, methylamino, dimethylamino, halogen, hydroxy, oxo, cyano and trifluoromethyl.
Still yet even more preferred are compounds of the formula (I) as described immediately above and wherein:
R1 is phenyl, naphthyl, pyrrolidinyl, thiomorpholinyl or morpholinyl, wherein R1 is optionally substituted by one or more Ra;
Ra is selected from the group consisting of a bond, C1-3 alkyl, pyrrolyl, imidazolyl, indolyl, benzimidazolyl, methoxy, methoxycarbonyl, t-butoxycarbonylamino, C1-3 alkylsulfonylamino, amino wherein the nitrogen atom may be independently mono or di-substituted by C1-3 alkyl, halogen, hydroxy, cyano and carboxy, Ra may be further optionally substituted by one or more Rb;
Rb is selected from the group consisting of methoxy, halogen and hydroxy;
Rc is selected from the group consisting of a bond, methyl, C3-6 cycloalkyl, C7-8 bicycloalkyl, phenyl, naphthyl, tetrahydronaphthyl, indanyl, C1-4 alkoxy, C1-3 alkanoylamino, methylthio, halogen, hydroxy, oxo, carboxy and cyano, Rc may be further optionally substituted by one or more Rd;
Rd is selected from the group consisting of C1-3 alkyl, phenyl, methoxy, halogen and hydroxy;
R6 is hydrogen;
Re is selected from the group consisting of a bond, C5-6 cycloalkyl, phenyl, C1-5 alkoxy, C1-5 alkylamino, pyrrolidinyl, piperidinyl, naphthyl, thienyl, indolyl, methoxy, benzyloxy, methylthio, benzylthio, methoxycarbonylamino, halogen, hydroxy, carboxy and cyano, Re may be further optionally substituted by one or more Rf; and
Rf is selected from the group consisting of C1-5 alkyl, C3-6 cycloalkyl, phenyl optionally substituted by halogen, methoxy, phenoxy, benzyloxy, methoxycarbonyl, halogen, hydroxy and carboxy.
R6 and R7 together with the carbon they are attached form a cyclopropyl ring or heterocyclic ring selected from the group consisting of pyrrolidinyl and piperidinyl, the cyclopropyl or heterocyclic ring being optionally substituted with one or more Rg;
Rg is selected from the group consisting of a bond, C1-8 alkyl, C3-8 cycloalkyl, C7-8 bicycloalkyl, benzyl, xcex1-tetrahydronaphthyl, xcex1-indanyl, tetrahydropyranyl, tetrahydrothiopyranyl and amino wherein the nitrogen atom may be independently mono or di-substituted by C1-5 alkyl, C3-6 cycloalkyl, benzyl or benzoyl, Rg may be further optionally substituted by one or more Rh; and
Rh is selected from the group consisting of C1-5 alkyl, C3-7 cycloalkyl, phenyl, benzyl, benzyloxy, tetrahydropyranyl, heteroaryl selected from the group consisting of thienyl, pyridinyl, indolyl, pyrrolyl and benzimidazolyl, halogen, hydroxy, oxo, cyano or trifluoromethyl, may be further substituted by Ri; and
Ri is C1-8 alkyl and halogen.
Even much more preferred are compounds of the formula (Ia) as described immediately above and wherein:
R1 is phenyl, morpholinyl, thiomorpholinyl or pyrrolidinyl, R1 is optionally substituted by one or more Ra;
Ra is selected from the group consisting of C1-3 alkyl, methoxy, C1-3 alkylsulfonylamino, halogen, hydroxy, cyano and trifluoromethyl;
R5 is C1-3 alkyl wherein R5 is optionally substituted by one or more Rc;
Rc is selected from the group consisting of C3-6 cycloalkyl, C7-8 bicycloalkyl, phenyl, naphthyl, xcex2-tetrahydronaphthyl or xcex2-indanyl, Rc may be further optionally substituted by one or more Rd;
Rd is selected from the group consisting of methyl, methoxy and halogen;
R7 is C1-5 alkyl wherein R7 is optionally substituted by one or more Re;
Re is selected from the group consisting of phenyl, naphthyl, C1-5 alkoxy, C1-5 alkylamino, pyrrolidinyl and piperidinyl, Re may be further optionally substituted by one or more Rf; and
Rf is selected from the group consisting of C1-5 alkyl, C3-6 cycloalkyl, phenyl optionally substituted with halogen, halogen and hydroxy.
or R6 and R7 together with the carbon they are attached form a cyclopropyl ring or heterocyclic ring selected from the group consisting of piperidinyl and pyrrolidinyl, the cyclopropyl or heterocyclic ring being optionally substituted with one or more Rg; and
Rg is selected from the group consisting of C1-8 alkyl, C3-8 cycloalkyl, C7-8 bicycloalkyl, benzyl, xcex1-tetrahydronaphthyl, xcex1-indanyl, tetrahydropyranyl, tetrahydrothiopyranyl and amino group wherein the nitrogen atom may be independantly mono or disubstuituted by C1-5 alkyl or C3-6 cycloalkyl,; Rg may be further optionally substituted by one or more Rh; and
Rh is selected from the group consisting of C1-5 alkyl, C3-7 cycloalkyl, phenyl, benzyl, benzyloxy, thienyl, pyrrolyl, indolyl, pyridinyl, halogen, hydroxy, cyano and trifluoromethyl; Rh may be further optionally substituted by one or more Ri; and
Ri is C1-5 alkyl and halogen.
Yet even much more preferred are compounds of the formula (Ia) as described immediately above and wherein:
R1 is 4-morpholinyl or pyrrolidinyl, wherein R1 is optionally substituted by one or more Ra;
Ra is C1-3 alkylsulfonylamino;
R5 is C1-3 alkyl wherein R5 is optionally substituted by one or more Rc;
Rc is selected from the group consisting of C5-6 cycloalkyl, C7-8 bicycloalkyl, xcex2-tetrahydronaphthyl and xcex2-indanyl, Rc may be further optionally substituted by one or more Rd;
Rd is selected from the group consisting of methyl, methoxy and halogen;
R7 is C1-5 alkyl wherein R7 is optionally substituted by one or more Re;
Re is selected from the group consisting of C1-5 alkoxy, C1-5 alkylamino, pyrrolidinyl and piperidinyl, Re may be further optionally substituted by one or more Rf; and
Rf is selected from the group consisting of C1-5 alkyl, C3-6 cycloalkyl, phenyl optionally substituted with halogen, halogen and hydroxy.
or R6 and R7 together with the carbon they are attached form heterocyclic ring selected from the group consisting of piperidinyl and pyrrolidinyl, the heterocyclic ring being optionally substituted with one or more Rg; and
Rg is selected from the group consisting of C1-8 alkyl, C3-8 cycloalkyl, C7-8 bicycloalkyl, benzyl, xcex1-tetrahydronaphthyl, xcex1-indanyl, tetrahydropyranyl and tetrahydrothiopyranyl; Rg may be further optionally substituted by one or more Rh; and
Rh is selected from the group consisting of C1-5 alkyl, C3-7 cycloalkyl, phenyl, pyridinyl, indolyl, thienyl, halogen, hydroxy, cyano and trifluoromethyl; Rh may be further optionally substituted by one or more Ri;
Ri is selected from the group consisting of C1-3 alkyl and halogen.
Ultimately preferred are compounds of the formula (Ia) as described immediately above and wherein:
R1 is 4-morpholinyl;
R5 is C1-3 alkyl wherein R5 is optionally substituted by one or more Rc;
Rc is selected from the group consisting of cyclohexyl, xcex2-tetrahydronaphthyl and xcex2-indanyl, Rc may be further optionally substituted by one or more Rd;
Rd is selected from the group consisting of methyl and halogen;
R7 is C1-5 alkyl wherein R7 is optionally substituted by one or more Re;
Re is selected from the group consisting of C1-2alkoxy and C1-2 alkylamino, Re may be further optionally substituted by one or more Rf;
Rf is selected from the group consisting of C1-3 alkyl, phenyl, halogen and hydroxy;
or R6 and R7 together with the carbon they are attached form a heterocyclic ring selected from the group consisting of piperidinyl and pyrrolidinyl, the heterocyclic ring being optionally substituted with one or more Rg; and
Rg is selected from the group consisting of C1-5 alkyl, C3-8 cycloalkyl, C7-8 bicycloalkyl, benzyl and xcex1-tetrahydronaphthyl; Rg may be further optionally substituted by one or more Rh; and
Rh is C1-5 alkyl, C3-7 cycloalkyl, thienyl, pyridinyl, indolyl, halogen, hydroxy and trifluoromethyl; Rh may be further optionally substituted by one or more Ri;
Ri is methyl.
The activity of particular compounds disclosed herein against cathepsin K may be determined without undue experimentation by one of ordinary skill in the art in view of the art, the guidance provided throughout this specification and by the art recognized methods referred to in the section entitled xe2x80x9cAssessment of Biological Properties.xe2x80x9d
The following subgeneric aspect of the compounds of the formula (Ia) is postulated to possess Cathepsin K activity:
The broadest embodiment of the formula (Ia) as described hereinabove and wherein
A is xe2x80x94C(O)xe2x80x94;
R1 is aryl or aryloxy wherein R1 is optionally substituted by one or more Ra;
R2 is hydrogen;
R3 is hydrogen;
R4 is hydrogen or lower alkyl;
R5 is alkyl optionally substituted by one or more Rc;
or R4 and R5 together with the carbon they are attached form a 3 to 7 membered carbocyclic ring optionally substituted with one or more Rd;
R6 is hydrogen or lower alkyl wherein one or more carbon atoms are optionally replaced by 1 to two heteroatoms selected from the group consisting of N,O and S;
R7 is hydrogen, alkyl wherein one or more carbon atoms are optionally replaced by 1 to two heteroatoms selected from the group consisting of N,O and S, cycloalkyl, aryl, heterocyclyl, heteroaryl or cyano, wherein R7 is optionally substituted by one or more Re;
R6 and R7 together with the carbon they are attached form a carbocyclic ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or heterocyclic ring selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl and tetrahydrothiopyranyl, the carbocyclic or heterocyclic ring being optionally substituted with one or more Rg;
Preferred cathepsin K inhibitors are those as described immediately above and wherein:
R1 is naphthyl, benzyloxy or phenoxy wherein R1 is optionally substituted by one or more Ra;
R4 is hydrogen or lower alkyl;
R5 is lower alkyl optionally substituted by one or more Rc;
or R4 and R5 together with the carbon they are attached form a 5 to 6 membered carbocyclic ring optionally substituted with one or more Rd;
R6 is hydrogen or lower alkyl wherein one or more carbon atoms are optionally replaced by N;
R7 is lower alkyl wherein one or more carbon atoms are optionally replaced by heteroatoms selected from the group consisting of N and O, R7 is optionally substituted by one or more Re;
R6 and R7 together with the carbon they are attached form a heterocyclic ring selected from the group consisting of pyrrolidinyl and piperidinyl each being optionally substituted with one or more Rg.
Most preferred cathepsin K inhibitors are those as described immediately above and wherein:
R4 is hydrogen or lower alkyl;
R5 is C1-4 alkyl optionally substituted by one or more Rc;
or R4 and R5 together with the carbon they are attached form a cyclohexyl ring optionally substituted with one or more Rd;
R7 is lower alkyl wherein one or more carbon atoms are optionally replaced by heteroatoms selected from the group consisting of N and O or benzyloxy;
R6 and R7 together with the carbon they are attached form pyrrolidinyl optionally substituted with one or more Rg.
The following are representative compounds of the invention:
4-Methyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid (2-benzyloxy-1-cyano-ethyl)-amide. MS: m/z=402 M+1;
N-(Benzyloxymethyl-cyano-methyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-(1-Cyano-3-phenyl-propyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=426 M+1;
4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid (2-benzyloxy-1-cyano-ethyl)-amide. MS: m/z=416 M+1;
4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid (1-cyano-3-phenyl-propyl)-amide. MS: m/z=400 M+1;
2-(Morpholine-4-carbonyl)-cyclohexanecarboxylic acid (benzyloxymetbyl-cyano-methyl)-amide;
N-(2-Benzyloxy-1-cyano-ethyl)-4-morpholin-4-yl-2-naphthalen-2-ylmethyl-4-oxo-butyramide. MS: m/z=486 M+1;
N-[2-(4-Chloro-benzyloxy)-1-cyano-ethyl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=477 M+1;
N1-(Benzyloxymethyl-cyano-methyl)-N4-[4-(5-chloro-H-benzoimidazol-2-yl)-phenyl]-2-cyclohexylmethyl-succinamide;
N4-(4-Acetylamino-phenyl)-N1-(2-benzyloxy-1-cyano-ethyl-2-cyclohexylmethyl-succinamide. MS: m/z=505 M+1;
N-(cyano-1-methyl-piperidin-4-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-(cyano-cyclopropyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-(cyano-1-benzyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl)-amide. MS: m/z=407 M+1;
4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid (1-benzyl-4-cyano-piperidin-4-yl)-amide. MS: m/z=455 M+1;
N-(1-Benzyl-4-cyano-piperidin4-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=481 M+1;
N-[1-(3-Benzyloxy-benzyl)-3-cyano-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=573 M+1;
N-(3-Cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=473 M+1;
N-[3-Cyano-1-(2,6-difluoro-benzyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin4-yl-4-oxo-butyramide. MS: m/z=503 M+1;
N-[3-Cyano-1-(3,5-difluoro-benzyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=503 M+1;
N-[3-Cyano-1-(3-trifluoromethyl-benzyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: mn/z=535 M+1;
N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=459 M+1;
4,4-Dimethyl-2-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-pentanoic acid (3-cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-amide. MS: m/z=460 M+1;
4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid (3-cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-amide. MS: m/z=447 M+1;
4,4-Dimethyl-2-(2-oxo-2-piperidin-1-yl-ethyl)-pentanoic acid (3-cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-amide. MS: m/z=445 M+1;
4,4-Dimethyl-2-(2-oxo-2-thiomorpholin-4-yl-ethyl)-pentanoic acid (3-cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-amide. MS: m/z=463 M+1;
N-(3-cyano-1-(3,3-dimethyl-butyl)-pyrrolidin-3-ylcarbamoyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-(3-Cyano-1-isopropyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=419 M+1;
N-(3-Cyano-1-methyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=391 M+1;
N-[3-Cyano-1-(1-ethyl-propyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=447 M+1;
N-(3-Cyano-1-isobutyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=433 M+1;
N-(3-Cyano-1-cyclopropylmethyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=431 M+1;
N-(3-Cyano-1-phenethyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=481 M+1;
N-(3-Cyano-1-methyl-piperidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=405 M+1;
N-[3-Cyano-1-(4-methyl-cyclohexyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=473 M+1;
N-(3-Cyano-1-propyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=419 M+1;
N-(3-Cyano-1-cyclopentyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=445 M+1;
N-(1-cyano-3-piperidin-1-yl-propyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
(4R)-N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-(1-methyl-cyclohexylmethyl)-4-morpholin-4-yl-4-oxo-butyramide;
N-[1-Cyano-3-(cyclohexyl-ethyl-amino)-propyl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=475 M+1;
N-[3-(Benzyl-isopropyl-amino)-1-cyano-propyl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=497 M+1;
N-[3-Cyano-1-(1H-indol-2-ylmethyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N4-Carbamoylmethyl-N1-(3-cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-N4-methyl-succinamide;
N-(3-Cyano-1-cycloheptyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=473 M+1;
N-[3-Cyano-1-(1,2,3,4-tetrahydro-naphthalen-1-yl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=507 M+1;
N-(1-Bicyclo[2.2.1]hept-2-yl-3-cyano-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=471 M+1;
N-(4-Cyano-1-propyl-piperidin-4-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=433 M+1;
N-(1-Benzyl-4-cyano-piperidin-4-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=487 M+1;
N-[3-Cyano-1-(tetrahydro-pyran-4-yl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide, MS: m/z 461=M+1;
N-[3-Cyano-1-(tetrahydro-thiopyran-4-yl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide, MS: m/z 477=M+1;
N-[3-Cyano-1-(tetrahydro-thiopyran-4-yl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide, MS: m/z 477=M+1;
N-[3-Cyano-1-(2-phenyl-benzyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide; MS, m/z 543=M+1;
N-[3-Cyano-1-(3-phenyl-benzyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide; MS, m/z 543=M+1;
N-{1-[(benzyl-methyl-amino)-methyl]-1-cyano-3-phenyl-propyl}-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-(4-Cyano-1,2-dimethyl-piperidin-4-yl)-2-cycloheyxlmethyl-4-morpholin-4-yl-4-oxo-butyramide;
(4R)-N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-(4-methyl-cyclohexylmethyl)-4-morpholin-4-yl-4-oxo-butyramide;
N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-4-morpholin-4-yl-4-oxo-2-(trans-4-phenyl-cyclohexylmethyl)-butyramide;
2-Bicyclo[4.1.0]hept-7-ylmethyl-N-(3-cyano-1-cyclohexyl-pyrrolidin-3-yl)-4-morpholin-4-yl-4-oxo-butyramide;
2-Bicyclo[4.1.0]hept-7-ylmethyl-N-(4-cyano-1-methyl-piperidin-4-yl)-4-morpholin-4-yl-4-oxo-butyramide;
N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-4-morpholin-4-yl-4-oxo-2-(1,2,3,4-tetrahydro-naphthalen-2-ylmethyl)-butyramide; MS, m/z 507=M+1;
N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-indan-2-ylmethyl-4-morpholin-4-yl-4-oxo-butyramide; MS, m/z 493=M+1;
N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-cyclopentylmethyl-4-morpholin-4-yl-4-oxo-butyramide; MS, m/z 445=M+1;
[2-Cyano-2-(2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyrylamino)-ethyl]-carbamic acid tert-butyl ester;
N-{Cyano-[(cyclohexyl-ethyl-amino)-methyl]-methyl}-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-{Cyano-[(dibenzylamino)-methyl]-methyl}-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-{[(Benzyl-ethyl-amino)-methyl]-cyano-methyl}-2-cyclohexylmethyl-4-morpholin4-yl-4-oxo-butyramide;
N-(Cyano-piperidin-1-ylmethyl-methyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
{1-[3-(1-Benzyl-3-cyano-pyrrolidin-3-yl carbamoyl)-4-cyclohexyl-butyryl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester. MS: m/z=566.5 M+1;
{I-[3-(3-Cyano-1-cyclohexyl -pyrrolidin-3-yl carbamoyl)-4-cyclohexyl-butyryl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester. MS: m/z=558.6 M+1;
N-(1-Benzyl-3-cyano-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-(3-dimethylamino-pyrrolidin-1-yl)-4-oxo-butyramide. MS: m/z=494.5 M+1;
N-(1-Benzyl-3-cyano-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-(3-methanesulfonylamino-pyrrolidin-1-yl)4-oxo-butyramide. MS: m/z=544.4 M+1;
N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-(3-methanesulfonylamino-pyrrolidin-1-yl)-4-oxo-butyramide. MS: m/z=536.4 M+1;
N-[(3S)-3-Cyano-1-trans-(4-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-Cyano-1-trans-(4-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-cis-(4-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-Cyano-1-cis-(4-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-trans-(4-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-Cyano-1-trans-(4-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-cis-(4-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-Cyano-1-cis-(4-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[1-trans-(4-tert-Butyl-cyclohexyl)-(3S)-3-cyano-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[1-trans-(4-tert-Butyl-cyclohexyl)-(3R)-3-cyano-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[1-cis-(4-tert-Butyl-cyclohexyl)-(3S)-3-cyano-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[1-cis-(4-tert-Butyl-cyclohexyl)-(3R)-3-cyano-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-cyano-1-cis-(3-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-cyano-1-cis-(3-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-cyano-1-trans-(3-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-cyano-1-trans-(3-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-(3,3-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-Cyano-1-(3,3-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-cis-(3-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-Cyano-1-cis-(3-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl4-oxo-butyramide;
N-[(3S)-3-Cyano-1-trans-(3-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-Cyano-1-trans-(3-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-cis-(2-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-Cyano-1-cis-(2-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-trans-(2-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-Cyano-1-trans-(2-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-cis-(2-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-Cyano-1-cis-(2-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-trans-(2-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-Cyano-1-trans-(2-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-(2,2-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-Cyano-1-(2,2-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-(4,4-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl4-oxo-butyramide;
N-[(3 R)-3-Cyano-1-(4,4-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-(2-methyl-2-phenyl-propyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-Cyano-1-(2-methyl-2-phenyl-propyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(S)-Cyano-methyl-phenyl-methyl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(R)-Cyano-methyl-phenyl-methyl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(S)-Cyano-methyl-pyridin-4-yl-methyl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(R)-Cyano-methyl-pyridin-4-yl-methyl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-indan-2-ylmethyl-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-Cyano-1-indan-2-ylmethyl-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-(5-methyl-thiophen-2-ylmethyl)-pyrrolidin-3-yl]-(2S)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-(5-methyl-thiophen-2-ylmethyl)-pyrrolidin-3-yl]-(2S)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-Cyano-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide and
the pharmaceutically acceptable salts, esters or tautomers thereof.
Of the aforementioned compounds, preferred are the following:
4-Methyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid (2-benzyloxy-1-cyano-ethyl)-amide. MS: m/z=402 M+1;
N-(Benzyloxymethyl-cyano-methyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-(1-Cyano-3-phenyl-propyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=426 M+1;
4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid (2-benzyloxy-1-cyano-ethyl)-amide. MS: m/z=416 M+1;
4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid (1-cyano-3-phenyl-propyl)-amide. MS: m/z=400 M+1;
N-(2-Benzyloxy-1-cyano-ethyl)-4-morpholin-4-yl-2-naphthalen-2-ylmethyl-4-oxo-butyramide. MS: m/z=486 M+1;
N-[2-(4-Chloro-benzyloxy)-1-cyano-ethyl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=477 M+1;
N-(cyano-1-methyl-piperidin-4-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-(cyano-cyclopropyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-(cyano-1-benzyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-(1-Benzyl-4-cyano-piperidin-4-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=481 M+1;
N-[1-(3-Benzyloxy-benzyl)-3-cyano-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=573 M+1;
N-(3-Cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=473 M+1;
N-[3-Cyano-1-(2,6-difluoro-benzyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=503 M+1;
N-[3-Cyano-1-(3,5-difluoro-benzyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=503 M+1;
N-[3-Cyano-1-(3-trifluoromethyl-benzyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=535 M+1;
N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=459 M+1;
4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid (3-cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-amide. MS: m/z=447 M+1;
4,4-Dimethyl-2-(2-oxo-2-thiomorpholin-4-yl-ethyl)-pentanoic acid (3-cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-amide. MS: m/z=463 M+1;
N-(3-cyano-1-(3,3-dimethyl-butyl)-pyrrolidin-3-ylcarbamoyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-(3-Cyano-1-isopropyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=419 M+1;
N-(3-Cyano-1-methyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=391 M+1;
N-[3-Cyano-1-(1-ethyl-propyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=447 M+1;
N-(3-Cyano-1-isobutyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=433 M+1;
N-(3-Cyano-1-cyclopropylmethyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=431 M+1;
N-(3-Cyano-1-phenethyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=481 M+1;
N-(3-Cyano-1-methyl-piperidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=405 M+1;
N-[3-Cyano-1-(4-methyl-cyclohexyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=473 M+1;
N-(3-Cyano-1-propyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=419 M+1;
N-(3-Cyano-1-cyclopentyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=445 M+1;
(4R)-N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-(1-methyl-cyclohexylmethyl)-4-morpholin-4-yl-4-oxo-butyramide;
N-[1-Cyano-3-(cyclohexyl-ethyl-amino)-propyl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=475 M+1;
N-[3-(Benzyl-isopropyl-amino)-1-cyano-propyl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=497 M+1;
N-[3-Cyano-1-(1H-indol-2-ylmethyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N4-Carbamoylmethyl-N1-(3-cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-N4-methyl-succinamide;
N-(3-Cyano-1-cycloheptyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=473 M+1;
N-[3-Cyano-1-(1,2,3,4-tetrahydro-naphthalen-1-yl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=507 M+1;
N-(1-Bicyclo[2.2.1]hept-2-yl-3-cyano-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=471 M+1;
N-(4-Cyano-1-propyl-piperidin-4-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=433 M+1;
N-(1-Benzyl-4-cyano-piperidin-4-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=487 M+1;
N-[3-Cyano-1-(tetrahydro-pyran-4-yl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide, MS: m/z 461=M+1;
N-[3-Cyano-1-(tetrahydro-thiopyran-4-yl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide, MS: m/z 477=M+1;
N-[3-Cyano-1-(tetrahydro-thiopyran-4-yl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide, MS: m/z 477=M+1;
N-[3-Cyano-1-(2-phenyl-benzyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide; MS, m/z 543=M+1;
N-[3-Cyano-1-(3-phenyl-benzyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide; MS, m/z 543=M+1;
(4R)-N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-(4-methyl-cyclohexylmethyl)-4-morpholin-4-yl-4-oxo-butyramide;
2-Bicyclo[4.1.0]hept-7-ylmethyl-N-(3-cyano-1-cyclohexyl-pyrrolidin-3-yl)-4-morpholin-4-yl-4-oxo-butyramide;
2-Bicyclo[4.1.0]hept-7-ylmethyl-N-(4-cyano-1-methyl-piperidin-4-yl)4-morpholin-4-yl-4-oxo-butyramide;
N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-4-morpholin-4-yl-4-oxo-2-(1,2,3,4-tetrahydro-naphthalen-2-ylmethyl)-butyramide; MS, m/z 507=M+1;
N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-indan-2-ylmethyl-4-morpholin-4-yl-4-oxo-butyramide; MS, m/z 493=M+1;
N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-cyclopentylmethyl-4-morpholin-4-yl-4-oxo-butyramide; MS, m/z 445=M+1;
[2-Cyano-2-(2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyrylamino)-ethyl]-carbamic acid tert-butyl ester;
N-{Cyano-[(cyclohexyl-ethyl-amino)-methyl]-methyl}-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-{Cyano-[(dibenzylamino)-methyl]-methyl}-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-{[(Benzyl-ethyl-amino)-methyl]-cyano-methyl}-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-(Cyano-piperidin-1-ylmethyl-methyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
{1-[3-(1-Benzyl-3-cyano-pyrrolidin-3-yl carbamoyl)-4-cyclohexyl-butyryl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester. MS: m/z=566.5 M+1;
{1-[3-(3-Cyano-1-cyclohexyl -pyrrolidin-3-yl carbamoyl)-4-cyclohexyl-butyryl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester. MS: m/z=558.6 M+1;
N-(1-Benzyl-3-cyano-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-(3-dimethylamino-pyrrolidin-1-yl)-4-oxo-butyramide. MS: m/z=494.5 M+1;
N-(1-Benzyl-3-cyano-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-(3-methanesulfonylamino-pyrrolidin-1-yl)-4-oxo-butyramide. MS: m/z=544.4 M+1;
N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-(3-methanesulfonylamino-pyrrolidin-1-yl)-4-oxo-butyramide. MS: m/z=536.4 M+1;
N-[(3S)-3-Cyano-1-trans-(4-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-Cyano-1-trans-(4-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-cis-(4-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-Cyano-1-cis-(4-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-trans-(4-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-Cyano-1-trans-(4-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-cis-(4-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-Cyano-1-cis-(4-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl4-morpholin-4-yl-4-oxo-butyramide;
N-[1-trans-(4-tert-Butyl-cyclohexyl)-(3S)-3-cyano-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[1-trans-(4-tert-Butyl-cyclohexyl)-(3R)-3-cyano-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[1-cis-(4-tert-Butyl-cyclohexyl)-(3S)-3-cyano-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[1-cis-(4-tert-Butyl-cyclohexyl)-(3R)-3-cyano-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-cyano-1-cis-(3-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-cyano-1-cis-(3-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-cyano-1-trans-(3-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-cyano-1-trans-(3-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-(3,3-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-Cyano-1-(3,3-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-cis-(3-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-Cyano-1-cis-(3-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-trans-(3-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-Cyano-1-trans-(3-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-cis-(2-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-Cyano-1-cis-(2-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-trans-(2-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-Cyano-1-trans-(2-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-cis-(2-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-Cyano-1-cis-(2-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-trans-(2-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-Cyano-1-trans-(2-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-(2,2-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-Cyano-1-(2,2-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-(4,4-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-Cyano-1-(4,4-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl4-oxo-butyramide;
N-[(3S)-3-Cyano-1-(2-methyl-2-phenyl-propyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl4-oxo-butyramide;
N-[(3R)-3-Cyano-1-(2-methyl-2-phenyl-propyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-indan-2-ylmethyl-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-Cyano-1-indan-2-ylmethyl-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-(5-methyl-thiophen-2-ylmethyl)-pyrrolidin-3-yl]-(2S)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-(5-methyl-thiophen-2-ylmethyl)-pyrrolidin-3-yl]-(2S)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide and
N-[(3R)-3-Cyano-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.
Of the above-listed preferred compounds, the following are more preferred compounds of the invention:
N-(Benzyloxymethyl-cyano-methyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[2-(4-Chloro-benzyloxy)-1-cyano-ethyl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=477 M+1;
N-(cyano-1-benzyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-(3-Cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=473 M+1;
N-[3-Cyano-1-(2,6-difluoro-benzyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=503 M+1;
N-[3-Cyano-1-(3,5-difluoro-benzyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=503 M+1;
N-[3-Cyano-1-(3-trifluoromethyl-benzyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=535 M+1;
N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=459 M+1;
N-(3-cyano-1-(3,3-dimethyl-butyl)-pyrrolidin-3-ylcarbamoyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-(3-Cyano-1-isopropyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=419 M+1;
N-(3-Cyano-1-isobutyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=433 M+1;
N-(3-Cyano-1-cyclopropylmethyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=431 M+1;
N-(3-Cyano-1-phenethyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=481 M+1;
N-(3-Cyano-1-methyl-piperidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl4-oxo-butyramide. MS: m/z=405 M+1;
N-[3-Cyano-1-(4-methyl-cyclohexyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=473 M+1;
N-(3-Cyano-1-propyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=419 M+1;
N-(3-Cyano-1-cyclopentyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=445 M+1;
N-[3-Cyano-1-(1H-indol-2-ylmethyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-(3-Cyano-1-cycloheptyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=473 M+1;
N-[3-Cyano-1-(1,2,3,4-tetrahydro-naphthalen-1-yl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=507 M+1;
N-(1-Bicyclo[2.2.1]hept-2-yl-3-cyano-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=471 M+1;
N-[3-Cyano-1-(tetrahydro-pyran-4-yl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide, MS: m/z 461=M+1;
N-[3-Cyano-1-(tetrahydro-thiopyran-4-yl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide, MS: m/z 477=M+1;
N-[3-Cyano-1-(tetrahydro-thiopyran-4-yl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide, MS: m/z 477=M+1;
(4R)-N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-(4-methyl-cyclohexylmethyl)-4-morpholin-4-yl-4-oxo-butyramide;
2-Bicyclo[4.1.0]hept-7-ylmethyl-N-(3-cyano-1-cyclohexyl-pyrrolidin-3-yl)-4-morpholin-4-yl-4-oxo-butyramide;
N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-4-morpholin-4-yl-4-oxo-2-(1,2,3,4-tetrahydro-naphthalen-2-ylmethyl)-butyramide; MS, m/z 507=M+1;
N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-indan-2-ylmethyl-4-morpholin-4-yl-4-oxo-butyramide; MS, m/z 493=M+1;
N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-cyclopentylmethyl-4-morpholin-4-yl-4-oxo-butyramide; MS, m/z 445=M+1;
N-{Cyano-[(cyclohexyl-ethyl-amino)-methyl]-methyl}-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-(Cyano-piperidin-1-ylmethyl-methyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-trans-(4-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-cis-(4-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-trans-(4-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-cis-(4-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[1-trans-(4-tert-Butyl-cyclohexyl)-(3S)-3-cyano-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-cyano-1-cis-(3-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-cyano-1-trans-(3-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-cyano-1-trans-(3-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-(3,3-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-Cyano-1-(3,3-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-cis-(3-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-trans-(3-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-Cyano-1-trans-(3-isopropyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-cis-(2-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-trans-(2-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-cis-(2-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-trans-(2-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-(2,2-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-(4,4-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-(2-methyl-2-phenyl-propyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-Cyano-1-(2-methyl-2-phenyl-propyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-Cyano-1-indan-2-ylmethyl-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide and
N-[(3S)-3-Cyano-1-(5-methyl-thiophen-2-ylmethyl)-pyrrolidin-3-yl]-(2S)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.
Of the above-listed more preferred compounds, the following are most preferred compounds of the invention:
N-(cyano-1-benzyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=459 M+1;
N-(3-Cyano-1-cyclopropylmethyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=431 M+1;
N-(3-Cyano-1-phenethyl-pyrrolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=481 M+1;
N-[3-Cyano-1-(4-methyl-cyclohexyl)-pyrrolidin-3-yl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide. MS: m/z=473 M+1;
(4R)-N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-2-(4-methyl-cyclohexylmethyl)-4-morpholin-4-yl-4-oxo-butyramide;
N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)4-morpholin-4-yl-4-oxo-2-(1,2,3,4-tetrahydro-naphthalen-2-ylmethyl)-butyramide; MS, m/z 507=M+1;
N-[(3S)-3-Cyano-1-trans-(4-ethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3S)-3-cyano-1-trans-(3-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;
N-[(3R)-3-cyano-1-trans-(3-methyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide and
N-[(3S)-3-Cyano-1-(3,3-dimethyl-cyclohexyl)-pyrrolidin-3-yl]-(2R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide.
Any compounds of this invention containing one or more asymmetric carbon atoms may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. All such isomeric forms of these compounds are expressly included in the present invention. Each stereogenic carbon may be in the R or S configuration, or a combination of configurations.
Some of the compounds of formulas (I) and (Ia) can exist in more than one tautomeric form. The invention includes all such tautomers.
It shall be understood by one of ordinary skill in the art that all compounds of the invention are those which are chemically stable.
The invention includes pharmaceutically acceptable derivatives of compounds of formulas (I) and (Ia). A xe2x80x9cpharmaceutically acceptable derivativexe2x80x9d refers to any pharmaceutically acceptable salt or ester of a compound of this invention, or any other compound which, upon administration to a patient, is capable of providing (directly or indirectly) a compound of this invention, a pharmacologically active metabolite or pharmacologically active residue thereof.
In addition, the compounds of this invention include prodrugs of compounds of the formulas (I) and (Ia). Prodrugs include those compounds that, upon simple chemical transformation, are modified to produce the compounds of the invention. Simple chemical transformations include hydrolysis, oxidation and reduction. Specifically, when a prodrug of this invention is administered to a patient, the prodrug may be transformed into a compound of formula (I) and (Ia), thereby imparting the desired pharmacological effect.
In order that the invention herein described may be more fully understood, the following detailed description is set forth. As used herein, the following abbreviations are used:
BOC or t-BOC is tertiary butoxycarbonyl
t-Bu is tertiary butyl
DMF is dimethylformamide
EtOAc is ethyl acetate
THF is tetrahydrofuran
Ar is argon
EDC is 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride
HOBT is 1-hydroxybenzotriazole.
Also, as used herein, each of the following terms, used alone or in conjunction with other terms, are defined as follows (except where noted to the contrary):
The term xe2x80x9calkylxe2x80x9d refers to a saturated aliphatic radical containing from one to ten carbon atoms or a mono- or polyunsaturated aliphatic hydrocarbon radical containing from two to twelve carbon atoms, containing at least one double or triple bond, respectively. xe2x80x9cAlkylxe2x80x9d refers to both branched and unbranched alkyl groups. Preferred alkyl groups are straight chain alkyl groups containing from one to eight carbon atoms and branched alkyl groups containing from three to eight carbon atoms. More preferred alkyl groups are straight chain alkyl groups containing from one to six carbon atoms and branched alkyl groups containing from three to six carbon atoms. It should be understood that any combination term using an xe2x80x9calkxe2x80x9d or xe2x80x9calkylxe2x80x9d prefix refers to analogs according to the above definition of xe2x80x9calkylxe2x80x9d. For example, terms such as xe2x80x9calkoxyxe2x80x9d, xe2x80x9calkythioxe2x80x9d refer to alkyl groups linked to a second group via an oxygen or sulfur atom. xe2x80x9cAlkanoyl refers to an alkyl group linked to a carbonyl group (Cxe2x95x90O).
The term xe2x80x9ccycloalkylxe2x80x9d refers to the cyclic analog of an alkyl group, as defined above, optionally unsaturated and substituted. Preferred cycloalkyl groups are saturated cycloalkyl groups containing from three to eight carbon atoms, and more preferably three to six carbon atoms.
The term xe2x80x9carylxe2x80x9d refers to phenyl and naphthyl.
Each of the above defined xe2x80x9calkylxe2x80x9d, xe2x80x9ccycloalkylxe2x80x9d and xe2x80x9carylxe2x80x9d shall be understood to include their halogenated analogs.
The term xe2x80x9chaloxe2x80x9d refers to a halogen radical selected from fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloro and bromo.
The term xe2x80x9cheteroarylxe2x80x9d refers to a stable 5-8 membered (but preferably, 5 or 6 membered) monocyclic or 8-11 membered bicyclic aromatic heterocycle radical. Each heterocycle consists of carbon atoms and from 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. The heterocycle may be attached by any atom of the cycle, which results in the creation of a stable structure. Preferred heteroaryl radicals include, for example, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl,
The term xe2x80x9cheterocyclexe2x80x9d refers to a stable 5-8 membered (but preferably, 5 or 6 membered) monocyclic or 8-11 membered bicyclic heterocycle radical which may be either saturated or unsaturated, and is non-aromatic. Each heterocycle consists of carbon atoms and from 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. The heterocycle may be attached by any atom of the cycle, which results in the creation of a stable structure. Preferred heterocycle radicals include, for example, pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, piperazinyl, indolinyl, azetidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, hexahydropyrimidinyl, hexahydropyridazinyl, 1,4,5,6-tetrahydropyrimidin-2-ylamine, dihydro-oxazolyl, 1,2-thiazinanyl-1,1-dioxide, 1,2,6-thiadiazinanyl-1,1-dioxide, isothiazolidinyl-1,1-dioxide and imidazolidinyl-2,4-dione.
The terms xe2x80x9cheterocyclexe2x80x9d, xe2x80x9cheteroarylxe2x80x9d or xe2x80x9carylxe2x80x9d, when associated with another moiety, unless otherwise specified shall have the same meaning as given above. For example, xe2x80x9caroylxe2x80x9d refers to phenyl or naphthyl linked to a carbonyl group (Cxe2x95x90O).
Each aryl or heteroaryl unless otherwise specified includes it""s partially or fully hydrogenated derivative. For example, quinolinyl may include decahydroquinolinyl and tetrahydroquinolinyl, naphthyl may include it""s hydrogenated derivatives such as tetrahydranaphthyl. Other partially or fully hydrogenated derivatives of the aryl and heteroaryl compounds described herein will be apparent to one of ordinary skill in the art.
As used herein above and throughout this application, xe2x80x9cnitrogenxe2x80x9d and xe2x80x9csulfurxe2x80x9d include any oxidized form of nitrogen and sulfur and the quaternized form of any basic nitrogen.
In order that this invention be more fully understood, the following examples are set forth. These examples are for the purpose of illustrating preferred embodiments of this invention, and are not to be construed as limiting the scope of the invention in any way.
The examples which follow are illustrative and, as recognized by one skilled in the art, particular reagents or conditions could be modified as needed for individual compounds. Starting materials used in the scheme below are either commercially available or easily prepared from commercially available materials by those skilled in the art.
The invention also provides processes of making the present novel compounds. Compounds of the invention may be prepared by methods described below. Standard peptide coupling, protection and deprotection reactions (see for example M. Bodanszky, The Practice of Peptide Synthesis, Springer-Verlag, 1984) are employed in these syntheses. Alkylated succinic acid derivatives used as starting materials are either commercially available or easily prepared by methods known to those skilled in the art. For example succinate derivatives may be alkylated by treatment with a suitable alkylating agent such as an alkyl halide in the presence of a suitable base such as lithium diisopropyl amide. If the succinate derivative contains a chiral auxiliary, for example a succinic acid chiral oxazolidine amide, a chiral alkylated succinate derivative can be obtained as described by Azam et al. (J. Chem. Soc. Perkin Trans. 1, 1996, 621) and Evans et al. (J. Am. Chem. Soc., 1981, 103, 2127). Alternatively, racemic alkylated succinate derivatives may be resolved by methods known to those skilled in the art if desired, for example by selective enzymatic hydrolysis as described by Oikawa et al. (Tetrahedron Lett., 1996, 37, 6169), Wirz et al. (Tetrahedron Asymmetry, 1997, 8, 187) and Ozaki et al. (Chem. Lett., 1997, 741).
Compounds of the invention in which R1 is an amino group or a heterocyclyl group containing a nitrogen that forms an amide bond with A (A=xe2x80x94C(O)xe2x80x94) of formula I may be prepared as described below and illustrated in Scheme I. 
A succinic acid monoester, for example a methyl ester as shown, is reacted with the desired amine R1H under standard peptide coupling conditions. An example of standard coupling conditions would be combining the starting materials in the presence of a coupling reagent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) with 1-hydroxybenzotriazole (HOBT), in a suitable solvent such as DMF or methylene chloride. A base such as N-methylmorpholine may be added. The resulting amide ester is hydrolyzed in aqueous base or acid. A suitable co-solvent such as THF or MeOH may be added. The resulting acid is then coupled with an amino nitrile under standard peptide coupling conditions as described above to provide the desired compound of formula (I). Alternately, one may couple the acid with an amino amide and then react the resulting amide with a suitable dehydrating agent such as cyanuric chloride in a suitable solvent such as DMF to provide the desired nitrite of formula (I).
Compounds of the invention in which R1 is alkyl or cycloalkyl may be prepared by reacting a succinic acid ester derivative, for example a methyl ester as shown below, containing an activated amide, for example a N-methoxy-N-methylamide (Solladic-Cavallo et al., Tetrahedron Asymmetry, 1996, 7, 1797), or a N-imidazolium-N-methylamide (De Las Heras et al., Tetrahedron Lett., 1997, 38, 1817) with a suitable organometallic reagent, such as an alkylmagnesium bromide (Scheme II). The resulting ketoester is then carried forth as described for the amide ester intermediate in Scheme I. 
Compounds of the invention in which R1 is aryl or heteroaryl may be prepared by reacting a suitable aryl or heteroaryl organometallic reagent with an activated amide as described above for R1=alkyl or cycloalkyl. In addition, an acyl halide, for example an acid chloride, may be used in place of an activated amide. Suitable aryl or heteroaryl organometallic reagents for reaction with acyl halides are known in the art and include aryl magnesium bromides (F. Babudri et al., Tetrahedron, 1996, 52, 13513), aryl lithium reagents in the presence of ZnCl2 (C. Kim et al., Tetrahedron Lett., 1994, 35, 3017) and aryl stannanes under Pd catalyzed Stille coupling conditions (M. J. Plunkett et al., J. Am. Chem. Soc., 1995, 117, 3306).
A method which may be used to stereoselectively prepare alkylated succinic acid derivatives, useful in the procedures described in Schemes I and II, is illustrated in Scheme III. 
In this procedure, a carboxylic acid bearing R4 and R5 is coupled with a chiral auxiliary group known in the art (see for example D. Evans et al., J. Am. Chem. Soc., 1990, 4011; D. Evans et al., J. Am. Chem. Soc., 1981, 2127, 103; D. Evans et al., Tetrahedron Lett, 1987, 6141; D. Evans et al., Tetrahedron Lett, 1987, 1123), such as (S)-(xe2x88x92)-4-isopropyl-2-oxazolidinone as illustrated in Scheme III. Suitable coupling conditions would include first converting the carboxylic acid to an acid chloride, for example by reaction with oxalyl chloride and DMF in a suitable solvent such as methylene chloride at about 0xc2x0 C. to room temperature. The acid chloride may then be coupled to the oxazolidinone in a suitable solvent, such as THF, in the presence of a suitable base, such as n-BuLi at about xe2x88x9278xc2x0 C. to room temperature.
The resulting product is then alkylated with a halomethylcarbonyl compound bearing R1, R2 and R3 in a suitable solvent such as THF, in the presence of a suitable base, such as sodium bis(trimethylsilyl)amide at about xe2x88x9278xc2x0 C. to room temperature. The large group on the chiral auxiliary (the isopropyl group in the illustrated example) directs the alkylating group to the side opposite it providing predominantly one isomer at the alkylated carbon. The chiral auxiliary is then removed by methods known in the art, for example in the case illustrated, in a suitable solvent such as THF in the presence of water and a suitable peroxide such as 30% hydrogen peroxide at about 0xc2x0 C., providing the desired succinic acid derivative which may be used in the procedure outlined in Scheme I, or converted to the corresponding ester by methods known to those skilled in the art and used in the procedure outlined in Scheme II.
Compounds of the invention in which R1 is alkyl, cycloalkyl, aryl or heteroaryl and A is xe2x80x94C(O)xe2x80x94 may be reacted with a suitable reducing agent such as sodium borohydride to produce the corresponding compound where A is xe2x80x94C(OH)xe2x80x94
The synthetic examples below are illustrative of the methods used to prepare the compounds of the invention.